Token lurking Buffalonian chiming in here. I'm curious to see what you folks like to do, but I figured the advice of a local could be helpful on your next trip. I'll try to organize it by general sections of the Buffalo region. In keeping w. this thread I'm going to avoid mentioning the obvious beer places - Cole's, Goodbar, Pizza Plant, etc.
Elmwood Village/Allentown (This is the area Cole's is located in)
Food:
Left Bank -
http://www.leftbankrestaurant.com/ - 511 Rhode Island St, Buffalo - Very solid restaurant, reasonable prices. Reservations are usually a must for a table, but my wife & I usually show up, snag a seat at the bar & eat there. Good enough beer selection - Orval & Hennepin are the highlights in bottles, taps usually include Urquell, something from Sierra Nevada and 1 or 2 Flying Bison beers, along with stuff like Stella.
Bistro Europa -
http://europabuffalo.com/ - 484 Elmwood Avenue, Buffalo - Great great great place. Check out their website to see daily specials to get an idea of what they offer & prices. I don't believe they take reservations & the place is small so you may have to wait a bit. Beerwise they'll make that wait tolerable w. most of the Ommegang line, some Brooklyn & other NY State offerings.
Allen Street Hardware -
http://www.allenstreethardware.com/main.htm - 245 Allen, Buffalo. They used to only do Panini but they've expanded their menu with some grilled items & usually at least 1 fish & meat special. Cosy, but you should be able to snag a table as long as you aren't showing up on a Friday or Saturday night. Can get loud at night with live music (usually blues or jazz). Good enough beer selection - only 4 taps, one of which has been Ommegang Rare Vos (woo!) for a few months. Bottle list probably has 20-30 options - last time I was there they were running a special on N. Coast Old Rasputin for $5/bottle.
Stuff to do:
Albright Knox is cool, but don't miss out on other things going on in the immediate area:
Hallwalls Contemporary Art Center -
http://hallwalls.org/ - 341 Delaware Ave, Buffalo. See their website to get an idea of their programming
Squeaky Wheel -
http://www.squeaky.org/ - 712 Main St, Buffalo. See their website to get an idea of their programming
Big Orbit Gallery/Soundlab -
http://bigorbitgallery.org/ - 30 Essex St. Buffalo (Big Orbit), Corner of Pearl & Swan (Soundlab). See their website to get an idea of their programming
Shakespeare in the Park -
http://www.shakespeareindelawarepark.org/ - Delaware Park (adjacent to the Albright Knox). Over for the season, but free performances offered 6 nights a week
There are some cool shops along Elmwood and Allen street and over on Hertel, though I don't get to Hertel very often.
If you're into architecture check out
http://www.buffaloah.com/a/bamname.html - Things in this area will largely fall into West Side & North Park/Central Park on that page
Places to stay (aside from the chains on Delaware)
- Elmwood Village Bed & Breakfast -
http://www.elmwoodvillageinn.com/ - they have a horrible website, but they're half a mile from Cole's. I've heard its nice
- Beau Fleuve B&B -
http://www.beaufleuve.com/ - about 1.3 miles from Cole's.
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Downtown: There isn't too much happening downtown. Especially on weekends.
Stuff to do:
If you're into live theater check out
http://www.theatreallianceofbuffalo.com/#
Baseball games can be fun if thats your thing:
http://buffalo.bisons.milb.com/index.jsp?sid=t422 they're shockingly inexpensive - 6 bucks will usually get you in & the stands are usually empty enough that while your ticket says 'bleacher' you can sit wherever you want.
If cheering on 2 dudes beating the hell out of each other with 14,000 other people is your thing you'd love going to a lacrosse game. I think Toronto has a team in the same league.
http://www.bandits.com/
Tift Nature Preserve -
http://www.sciencebuff.org/tifft-nature-preserve/ - any birders here? Len?
Food:
Kinda stumped here. I'll usually shoot out to Allentown or Elmwood for a meal if I'm downtown. There is a Charlie the Butcher (think amazing roast beef sandwiches) in the Ellicott Square Building at 295 Main Street. Probably only there on Weekdays though.
Places to stay:
Um.. if you're looking to save money there is a hostel:
http://www.hostelbuffalo.com/test/
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North Buffalo/North of Buffalo (this is the Sheridan/Niagara Falls Boulevard section of town):
Food:
Shango. 3260 Main Street -
http://www.shangobistro.com/ - tasty stuff billed as "New Orleans Bistro" Solid beer list in terms of Bottles & the 4 or 5 taps they have. Had some great mussels here last time I went.
Amy's Place. 3234 Main St -
http://www.yelp.com/biz/amys-place-buffalo - Yes, its a college dive diner & yes, you'll probably have that 'Amy's Place smell' in your clothes when you leave but Amy's is great. Get the veggie wet shoes - fries covered in veggie chili & cheese. Freaking great. Also wonderful is the Margie Meal - marinated chicken, fries, tomatoes, garlic yogurt sauce & hot sauce rolled up in a pita. Cash only - but very inexpensive. I think they still do a 99 cent breakfast before 8am.
Stuff to do:
Good question. For the most part its suburban strip mall hell. Go to Target or something.
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East of Buffalo (Galleria Mall area)
Food:
So many chains.. ugh.
But there is hope if you find yourself at the Galleria Mall. Head to Kentucky Greg's -
http://www.kentuckygregs.com/ - 2186 George Urban Blvd - for what I think is the best BBQ in Buffalo. Not much in the way of ambiance, and nada in terms of beer (they've got all kinds there - miller, miller light AND heinekin) but man, do their beans sing.
Stuff to do:
Is it a Friday or Saturday morning? Head to Super Flea
http://tiny.cc/jcc4i - 2500 Walden Ave - where you can see more crap than you can shake a stick at. You probably won't buy anything, but its an experience.
I don't know what else - maybe buy a really big tv?
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South of the City:
I rarely go south of the city, so my recommendations are crummy here, but..
If you ski, check out the ski areas in Ellicottville
http://www.ellicottvilleny.com/
If you're in East Aurora I've heard that Bar Bill has amazing wings, though I haven't gotten there yet.
http://barbill.com/ 185 Main St. East Aurora
It occurs to me as I look at this that I've mostly told you where to eat. Which is usually my concern when I go to a new city

I'm sure other activities will pop into my mind later.
-rudy