The hemophilias are an attractive model for gene therapy because their clinical manifestations are attributable to the lack of a single protein that circulates in minute amounts in the plasma. Sustained therapeutic expression of factors VIII and IX has been achieved in preclinical studies using a wide range of gene transfer technologies targeted at different tissues. This achievement has led to six different phase I/II clinical trials that resulted in limited efficacy but minimal toxicity. Recombinant adeno-associated viral vectors appear most promising for hemophilia gene therapy; however, this review summarizes all the major gene therapy approaches used and outlines the future challenges.