The GAL4 protein of yeast activates the transcription of several genes involved in galactose metabolism. This event requires that GAL4 bind to upstream activation sites with the consensus sequence 5'-CGGN5(T/A)N5CCG-3'. We review the general requirements that must be met for a protein such as GAL4 to find and remain bound to its target site in vivo. Evidence is presented that the GAL4 DNA-binding domain itself has insufficient intrinsic sequence selectivity to fulfill the task of targeting GAL4 to the appropriate sites in a yeast genome. Possible mechanisms by which this selectivity is enhanced in vivo are discussed.