Planning is the key to maximizing your experience. First, book a hotel near the activities that most interest you. If you're here to see a Broadway-style show, get the view from the CN Tower, stroll the lakefront, stomp your feet at a Raptors game, or soak up some culture at the ballet, opera, or symphony, go for a room in or near Harbourfront. If food, shopping, or museums are your passion, affluent Yorkville might be better suited (bonus: it's at the axis of both major subway lines). To live like a local, wandering neighborhood streets and patronizing funky cafés and shops, consider the Queen West boutique hotels.
In a short trip you can do a lot but not everything. Decide on your priorities, and don't overbook. Allow time for wandering. Schedule coffee (or Ontario microbrew) breaks. Be realistic about your sightseeing style. If you tend to scour every inch of a museum, you could spend an entire afternoon at the ROM (Royal Ontario Museum); if you're selective, you can breeze through in an hour.
Plan your days geographically. Kensington and Chinatown make an excellent combo; High Park and The Beach, not so much.
Ditch the car and get a TTC day pass for unlimited travel on the subways and streetcars.