Considerable progress has been made in unraveling key pathogenetic steps in human leukemogenesis. In recent years, cytogenetic analyses and the molecular characterization of chromosomal breakpoints in patients with acute leukemia have proven that homeobox (HOX) genes, an evolutionarily highly conserved family of transcription factors, are critically involved in human leukemogenesis. HOX genes themselves, as well as their upstream regulators and cofactors, are implicated in the pathogenesis of leukemia, and experimental models using knock-in strategies or retrovirally induced overexpression of candidate genes have shown the leukemogenicity of homeobox genes. This review summarizes the recent advances in this field.