I could write a whole book on this but I won't.
* Downtown - One of the better downtowns in the country, but there are different areas of it you should know about.
The Loop which is south of the river is typically pretty boring but there are some good things about it. The reflecting bean you might see is there for example, which is within Millennium Park. The Chicago Athletic Association is now a boutique hotel with some cool bars and restaurant like the Cherry Circle Room and Cindy's. Awesome views of Millennium Park/Lake. The Virgin Hotel also has a decent rooftop, and there's ROOF at theWit hotel which is a decent clubby type of lounge. There's also some shopping on State Street.
Most of the nightlife downtown though happens north of the river in areas like River North and Gold Coast. Hubbard Street in River North for example is an area with a lot of bars (start near Hubbard & State street). Other streets around it like Kinzie, Illinois, etc will have it too. They have everything from dives to decent lounge-ish type of bars like Celeste to clubs a little further up near Ontario Street (like Sound Bar, Y Bar, etc), your average decent place like Rockit. A lot of food in the area. Gold Coast is my neighborhood which is pretty funny - there's a number of nicer lounge type of places but also some kind of more divey ones which have a lot of younger people at them. My favorite places around there are a little classier - places like the 2nd floor lounge at Le Colonial, Salone Nico (attached to Nico Osteria), Pump Room, 2nd floor of Maple & Ash, Le Bar, Sparrow, etc. Division Street has the younger, "crappier" bars - though there's been a few to open there which are kind of straying from that.
Streeterville, which is near where Navy Pier is, is kind of boring. A lot of things, but many chains, not a lot of GOOD nightlife (but some), etc.
Many parts of the city, especially downtown, are very walkable. Even if you are coming with a car, there's no reason to use it in areas like this if you're just staying in the area especially. Driving would pretty much be a waste of time and money. There are also cabs/uber/etc all over, trains, buses, etc.
* Food - Chicago is a food city and a lot of people in the Midwest know it for the hot dogs, pizza, etc but it's way more than that. As I mentioned before, deep dish might be well known but locals don't eat it that much. Lou Malnati's and Pequod's is my favorite though, but you can get just about anything in town. The city, including downtown, has a lot of great restaurants of all sorts of food. My suggestion is that if all you do when you come to Chicago is get deep dish and hot dogs, to branch out a bit. The city is incredibly more with food than that. There is a reason why it's one of only three US cities to have a michelin guide for dining. The West Loop (mostly west of the expressway) has some great restaurants and is a kind of up and coming, hot area at the moment.
There are also ethnic neighborhoods like Chinatown, Argyle Street area (Vietnamese), Devon Street (Indian), Greektown, many Mexican areas (like Pilsen), Puerto Rican (Humboldt Park - might be dangerous for most people - but also extends into other areas slightly for other Latin American food in the area like Logan Square), etc.
Neighborhoods like Wicker Park and Logan Square have some good food, nightlife, etc too. Wicker Park = Damen O'Hare Blue Line stop for that, and Logan Square has some good stuff not far from the California Blue Line stop. Things here tend to sway more on the hip side, though you can find more vanilla options too in an area like Wicker Park, Fun areas though. Some of the more "vanilla" areas that have some good activity would be Lakeview/Wrigleyville and Lincoln Park, and maybe Lincoln Square/Ravenswood for more laid back things.
I suggest if it's at all nice out that everyone should go to the lakefront, specifically downtown and north of Navy Pier. Also, if you want to see an awesome view without paying $25/person for it then I suggest going to the John Hancock Tower's 96th floor lounge. It's free to get up there and you can get some appetizer or a drink and much less expensive than the observation decks. Also, the view is better up there than the Sears (Willis) Tower. I suggest going before sundown.
* Safety - Chicago is on the news for crime many times (and there can be other reasons for that we won't talk about). The city is a tale of two cities though. Areas like the north side are relatively safe to very safe depending on where you are. Areas of the west and south sides though (not every area) can be dangerous. The area around U/C is very interesting as it looks kind of rough - and to the west a little bit it might be. My suggestion to people is to not go west, but east towards downtown is better. If someone asks you for money or anything like that on the street and you feel uncomfortable, ignore it. You don't need to say anything to them.
Tons more but it's hard to write since there's so much to do, eat, see, etc.