Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell neoplasms characterized by the driver mutations JAK2, CALR, and MPL. These mutations cause constitutive activation of JAK-STAT signaling, which is central to pathogenesis of MPNs. Next-generation sequencing has further expanded the molecular landscape allowing for improved diagnostics, prognostication, and targeted therapy. This review aims to address current understanding of the molecular diagnosis of MPN not only through improved awareness of the driver mutations but also the disease modifying mutations. In addition, other genetic factors such as clonal hematopoiesis of indeterminate potential (CHIP), order of mutation, and mutation co-occurrence are discussed and how these factors influence disease initiation and ultimately progression. How this molecular information is incorporated into risk stratification models allowing for earlier intervention and targeted therapy in the future will be addressed further. The genomic landscape of the MPN has evolved in the last 15 years with integration of next-generation sequencing becoming the gold standard of MPN management. Although diagnostics and prognostication have become more personalized, additional studies are required to translate these molecular findings into targeted therapy therefore improving patient outcomes.