We are planning a weekend in NYC and will be joined by a couple from San Diego who have never been there. What are the "don't miss" places we should visit as first time tourists? Should we get hotel rooms in the Times Square area? We would like to take in a show and see the main sites for this first visit. Your suggestion will be most welcome.

I think you should stay in Times Square only if you plan to see a lot of shows. But if so, you should!
Also I think you should definitely go to the top of the Empire State building. The views are magnificent.

Not everyone has the same "must sees" so it's pointless for us to decide what you and they should see w/o knowing anything about tastes. I lived in NYC for YEARS without going to the top of the ESB and still don't consider it a must see/do thing. What I do think is for a first visit that's a short weekend, taking one of the overview tours like nypartyshuttle.com or kingofnyc.com is a good way to see a lot and feel like you "saw" NYC.

Staying in Times Square is another issue of taste. I do agree with hilarygg that it absolutely makes sense, esp. for a weekend, if you plan on seeing 2 or more shows. There are some hotels though that are within a short walk of the theaters but don't give you the hectic feeling of being in Times Square (the Michelangelo, the Blakleyl, the Sofitel). But then others LOVE the hectic atmosphere of TS.

Check broadwaybox.com for discounts for theater tix before you buy full price.

With limited time in NYC, I'd suggest going to the Top of the Rock if having an ariel view of the city is something you are interested in and the ESB is not something that you just have an overwhelming desire to visit. Lines to get to the top of the ESB will run 1-3 hours, Top of the Rock allows you to pre-book entry windows in 15 minute increments (you can stay as long as you want once you are in) - much more efficient.

Times Square is the absolute LAST place I suggest you stay unless your sole activity is shows.

That area is crowded, dirty & loud -- by Manhattan standards!

I suggest experiencing Manhattan by neighborhood, with lots of walking. Get a good guidebook & flashmaps of Manhattan & Enjoy!

You may be wondering why you've received so few responses to such a basic question. Well, for one, it could be that your question is bit too broad. And secondly, perhaps you should do a bit of research and then come back with more specific questions.
A "don't miss" for me may not necessarily be a don't miss" for you!
So, the best suggestion is: Do some research!

As several people have mentioned - it's hard to give advice without knowing anything about you/your interests.

But - my rules for NYC for all:

Do NOT stay in Times Square unless you're there primarily for theater. It's a super busy business district that is loud garish and mobbed with people clogging the sidewalks at all hours. There are many better areas (do a search here or ask - but give us a budget and what you're looking for)

To see a show go to broadwaybox.com, find a show you like that has discounts, take the code and go to the regular online seller. Shows come up about 60 days in advance usually. doing this gets you better selection than waiting until you get to NNYC. If you want to see a specific hit show get tickets as soon as your travel dates are set.

See Top of the Rock versus the Empire State Building, since you can get timed tickets and avoid hours on line. Also - I think the views are better.

See some of the Met- the greatest cultural institution in the western hemisphere (go to the web site to pick a few departments you want to see)

See the Ellis Island Immigration Museum (the ferry there will also stop at Liberty Island, giving you a close up view of the Statue - but don;t bother getting off, since the lines are horrendous and you can see only a little bit of the inside of the Statue)

Spend some time in Central Park, either walking, biking or take a boat out on the lake

Tell us about you and we can reco things specific to your interests

I am jumping in on this post because I'm also planning a trip (May 24-29). Any suggestions for a hotel near Central Park for about $250?

I completely agree with going to the Top of the Rock vs. ESB. I went with four of my friends a few years ago and unlike what is implied in "Sleepless in Seattle," you DO not go in the front door and immediately ride an elevator to the top. Granted, the movie was done pre-security checks, but I couldn't believe how long it took us to inch our way through hallways and two elevators before we got to the top! Granted, we made the mistake of going there on our way to the train station and I swear my 70-year-old friend had six bottles of heavy booze in her bag, which we helped drag through the building, but it wasn't a pleasant experience....