Something I always suggest to my fellow travelers is taking a walking tour around your destination. Either with a company or just following one outline by your travel guide. This is a great way to familiarize yourself with not only the city, but the direction of things. It's easy to know North, East, South, West; but it's another to know "Oh the subway always exits on this side of an intersection!"
Also, walking tours can help you weed out some of the less necessary attractions, especially if it's guided by a local! They can tell you what's over priced and what is a great hidden treasure. If you're lucky, they may even make suggestions for dining.
I'm a huge fan of Sandman's and they seem to be adding new cities every year. If there is one at your vacation destination, take it! You won't regret it.
If you think you're going to wing it on your own with your travel guide book, then I suggest looking to see if your city has a Spy Map, they are just as good as a local guide with finding hip cafes or good restaurants. I'll be using on in Budapest, but I've used them before in Barcelona, Prague, and Dublin.
In the end, no matter where you go, walking your destination can be very rewarding. So next time you see one of those red double decker buses, just think how much they miss out from up there.