Recombinant adenoviruses can infect nondividing cells with high efficiency and are rapidly concentrated in the liver after systemic administration, making them attractive for use in liver-directed gene therapy. However, there are two hurdles to clinical application of these vectors. First, adenoviruses are episomal and have limited life spans within the cell. Second, host antiviral immune responses reduce the duration of vector persistence and preclude long-term transgene expression by repeated injection of the vector. Several strategies have been designed for abrogation of the specific antiadenoviral immune responses by modification of the host immune system or alteration of the vector. These strategies and the use of adenoviral vectors for the treatment of hereditary, infectious, and malignant diseases of the liver are discussed in this review.