Herpes simplex virus type 1 (HSV‑1) -based amplicon vectors have a transgene capacity of up to 150 kbp and can efficiently transduce many different cell types in culture and in vivo without causing cytopathic effects. However, these vectors do not support long-term transgene expression. Adeno-associated virus type 2 (AAV‑2)has the capacity to integrate its genome into a specific site on human chromosome 19, but AAV‑2-derived gene therapy vectors have a transgene capacity of only 4.5 kb. To combine the large transgene capacity of HSV‑1 with the potential for site-specific genomic integration and long-term transgene expression of AAV‑2, HSV/AAV hybrid vectors have been developed. This review describes the design, applications and limitations of these hybrid vectors. However, as HSV‑1 is a full helper virus for AAV‑2 replication, the main focus is the analysis of the molecular mechanisms of interaction between the two viruses. The knowledge of these interactions will have direct implications on the design of novel HSV/AAV hybrid vectors.