The human immunodeficiency virus (HIV) epidemic provides a rare opportunity to examine in detail the initial stages of a host-pathogen co-evolutionary struggle in humans. The genes encoding the human leukocyte antigen (HLA) class I molecules have a critical influence in the success or failure of the immune response against HIV. The particular HLA class I molecules expressed by each individual defines the type of cytotoxic T-lymphocyte (CTL) response that is made against the virus. This chapter describes the role of HLA class I and the CTL response in controlling HIV replication, and discusses the extent to which HIV has already adapted to those HLA class I molecules and CTL responses that are most effective in viral suppression. It is evident that viral mutations that enable HIV to evade the CTL response are indeed already accumulating in populations where the selecting HLA molecules are highly prevalent, indicating the dynamic and shifting nature of the evolutionary interplay between HIV and human populations.