One important outgrowth of molecular medicine is the development of technologies for the transfer of therapeutic genes to cells in culture and tissues in vivo, which promises to revolutionize both experimental biomedical science and the clinical practice of medicine. Fundamental obstacles must still be overcome to create safe and efficient gene delivery vectors specifically designed for individual tissue types, and special strategies will be required for direct in vivo gene transfer to neurons because these cells are postmitotic and cannot be removed for transduction. Herpes simplex virus type 1 (HSV-1), a neurotropic virus that naturally establishes a latent state in neurons, has many unique features that make it suitable as a gene transfer vector for the nervous system. In this review we describe the molecular biology of HSV-1, strategies for reducing potential pathogenesis of the recombinant vector, and methods for expressing transgenes from the vector genome. Gene transfer experiments using recombinant HSV-1-based vectors and defective HSV-1 vectors (amplicons) for gene transfer are also described and evaluated in terms of efficiency and safety.