Dysregulation of homeobox (HB)-containing genes is becoming increasingly recognized as the underlying basis of many hematologic malignancies. Expression of clustered HB (HOX) genes within the hematopoietic system, and enforced overexpression and knockout studies have provided support for the concept that these homeodomain-containing transcription factors play a significant role in the developmental biology of hematopoietic cells. Diverged HB (non-HOX) genes have recently been identified as either cofactors and/or accelerators of leukemic disease mediated by HOX genes or as bona fide oncogenes. In this review, we examine the evidence that supports a central role for HB genes in normal and malignant hematopoiesis, paying particular attention to the non-HOX class and the possible mechanisms through which they contribute to leukemic transformation.