The gametocyte, or sexual blood-stage, of the malaria parasite represents the only stage of the parasite that can be transmitted to the mosquito vector following sexual development within the infected bloodmeal. Little is known about the processes leading to this cellular differentiation and specialization. The recent completion of the Plasmodium genome, and subsequent transcriptome and proteome analyses have revealed for the first time a molecular map of the genes that are differentially regulated at the onset of and during gametocytogenesis. In this review, we outline the underlying mechanisms involved in this process, focusing on the transition between the asexual and the sexual blood-stages of the parasite.