Following infection, T cells differentiate into a heterogeneous population of effector T cells that can mediate pathogen clearance. A subset of these effector T cells possesses the ability to survive long term and mature into memory T cells that can provide long-term immunity. Understanding the signals that regulate the development of memory T cells is crucial to efforts to design vaccines capable of eliciting T cell-based immunity. CD4(+) T cells are essential in the formation of protective memory CD8(+) T cells following infection or immunization. However, until recently, the mechanisms by which CD4(+) T cells act to support memory CD8(+) T cell development following infection were unclear. Here, we discuss recent studies that provide insight into the multifaceted role of CD4(+) T cells in the regulation of memory CD8(+) T cell differentiation.