The molecular basis of polycythemia vera is discussed in the context of the JAK2 V617F mutation, in our view the most important advance in understanding the pathogenesis of polycythemia vera. This chapter discusses the nature of the JAK2 V617F mutation including the studies demonstrating its role in erythropoietin independence and hypersensitivity and endogenous erythroid colony formation. The evolving evidence that JAK2 V617F is not specific for polycythemia vera pathogenesis and the development of disease phenotype is presented as well as alternative candidates for pathogenic mutations such as the protein tyrosine phosphatases and SOCS-3. Finally, the clinical correlations and implications of the JAK2 V617F mutation are discussed.