Analysis of the nonclassic actions of vitamin D₃ has highlighted a wide range of target tissues for the hormone 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]. Systemic or locally produced 1,25(OH)₂D₃ may play a role in modulating cell development processes such as hematopoiesis. The mechanisms by which 1,25(OH)₂D₃ achieves this are discussed in this review. In particular, data from our laboratories suggest that 1,25(OH)₂D₃ does not provide a deterministic signal for monocyte differentiation. Rather, the hormone acts as a permissive agent for myeloid precursor cells to enter a genetically determined terminal maturation pathway. The effiacy of 1,25(OH)₂D₃ in leukemia therapy has been improved by the development of novel vitamin D analogues that have potent antiproliferative activity and low hypercalcemic side effects. Another solution to the problem of side effects is to enhance specifically the antiproliferative effects of 1,25(OH)₂D₃. A novel mechanism within hematopoiesic cells that governs their responsiveness to the antiproliferative/differentiative actions of 1,25(OH)₂D₃ outlined.