We summarize the current knowledge on molecular alterations in myeloproliferative disorders (MPD), in particular altered in vitro responses of progenitor cells, cytokine signaling, gene expression patterns and genetic lesions. Newly characterized markers, such as altered expression of polycythemia rubra vera-1 (PRV-1) and the thrombopoietin receptor (c-MPL) as well as deletions on chromosome 20q (del20q) and loss of heterozygosity on chromosome 9p (9pLOH) provide an opportunity to diagnose and identify subpopulations of MPD patients. Furthermore, we review familial syndromes that share phenotypic features with sporadic MPD. In some of these families, mutations in the genes for thrombopoietin (TPO), c-MPL, EPO-receptor and the von Hippel-Lindau (VHL) gene have been shown to cause the disease. However, in the majority of familial cases the molecular causes remain unknown. Some of these families display clonal hematopoiesis and other features previously only found in sporadic MPD. Elucidating the molecular defect(s) in these pedigrees will likely be relevant for understanding sporadic MPD pathogenesis.