During B and T cell development, haemopoietic progenitor cells (HPCs) must pass through a series of developmental checkpoints to ensure that the emerging mature lymphocytes are tolerant to self-antigens, while capable of recognising foreign antigens. Protein kinase Cα (PKCα) is a ubiquitously expressed serine/threonine protein kinase that has been implicated in the regulation of a variety of cellular functions including proliferation, differentiation and apoptosis in response to a diverse range of stimuli. In an effort to define the role of PKCα during lymphocyte lineage commitment and differentiation, we manipulated mouse-derived HPCs to stably express plasmids encoding kinase-active or -inactive PKCα constructs and then assessed their developmental potential by placing the cells in T cell or B cell generation systems in vitro and in vivo. In this way, we demonstrated that PKC activation is critical for T cell progenitors to successfully transit through the primary developmental checkpoint (β-selection), as expression of a plasmid-encoding kinase-inactive PKCα (PKCα-KR) in HPCs, resulted in an early block in T cell development. To address whether PKCα played a critical role during the early stages of B cell development, PKCα-KR-expressing HPCs were cultured in a B cell development system. Surprisingly, analysis of the developing cells revealed the spontaneous generation of B lineage cells that possess the key hallmark features of human CLL cells at both the phenotypic and molecular level. This finding indicates that inhibition of PKCα activity in B lineage cells serves as an oncogenic trigger, initiating the development of CLL. Taken together, these studies reveal that subversion of PKCα signalling can have distinct functional outcomes on B and T lineage cells. Our recent data defining the cellular and molecular mechanisms that control these events will be discussed.