The initiation and evolution of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are driven by genomic events that disrupt multiple genes controlling hematopoiesis. Human genetic studies have discovered germline mutations in single genes that instigate familial MDS/AML. The best understood of these genes encode transcription factors, such as GATA-2, RUNX1, ETV6, and C/EBPα, which establish and maintain genetic networks governing the genesis and function of blood stem and progenitor cells. Many questions remain unanswered regarding how genes and circuits within these networks function in physiology and disease and whether network integrity is exquisitely sensitive to or efficiently buffered from perturbations. In familial MDS/AML, mutations change the coding sequence of a gene to generate a mutant protein with altered activity or introduce frameshifts or stop codons or disrupt regulatory elements to alter protein expression. Each mutation has the potential to exert quantitatively and qualitatively distinct influences on networks. Consistent with this mechanistic diversity, disease onset is unpredictable and phenotypic variability can be considerable. Efforts to elucidate mechanisms and forge prognostic and therapeutic strategies must therefore contend with a spectrum of patient-specific leukemogenic scenarios. Here we illustrate mechanistic advances in our understanding of familial MDS/AML syndromes caused by germline mutations of hematopoietic transcription factors.