Remember that a weekend is only two days long. A trip that sounds totally doable as you stare out the window daydreaming on an anxious Friday afternoon can lead to a weekend spent mostly sitting in traffic. Also, remember that travel time on Friday night often provides no indication of how long the drive will take on Sunday afternoon, when everyone is trying to head back all at once. Before you shove off for the weekend, talk to someone who has made the trek before. Many adventurous gamblers have jetted from L.A. to Vegas late Friday on a holiday weekend, not realizing that a trip that takes three hours on Friday night could take seven hours on Sunday. Many East Coast adventurers have spent most of their New York weekends transferring from trains to subways, and back again. Attempt only what you have time for. No one can hit every club in Portland or every bar in New Orleans in one weekend.
Remember, like General Douglas MacArthur, you shall return.