Studies of endogenous and engineered Ig genes in mice have begun to reveal some of the cis-acting regions that are involved in the somatic hypermutation of variable regions in vivo. These studies suggest that the initiation of transcription plays a role in this process. However, it will be difficult to identify and manipulate the individual genetic elements and the trans-acting proteins that regulate and target the mutational events using solely in vivo assays. These studies would be greatly facilitated if constructs containing the genetic elements that are essential for V-region mutation could be transfected into cultured cells and undergo high rates of V-region mutation in vitro, and if permissive and non-permissive cell lines could be identified. Such in vitro systems would also allow a detailed molecular and biochemical analysis of this process. Here, we discuss some of the in vitro systems that have been developed and use data from our own studies in cultured cells to illustrate the potential benefits of studying V-region hypermutation in model in vitro systems.