The discovery that an abnormally activated JAK-STAT signaling pathway is central to the pathogenesis of myeloproliferative neoplasms has promoted the clinical development of small-molecule JAK2 inhibitors. These agents have shown remarkable efficacy in disease control, but do not induce molecular remission; on the other hand, interferon holds the promise to target the putative hematopoietic progenitor cell initiating the disease. The presence of additional molecular abnormalities indicates a high molecular complexity of myeloproliferative neoplasms, and the need for simultaneously targeting different targets. Several drugs are currently under study as single agents and in combination. This review briefly describes the several in vitro and in vivo models of myeloproliferative neoplasms that are being used as preclinical models for drug development.