Current studies to define the mechanism by which vitamin D3 and analogs of vitamin D3 enhance the response to ionizing radiation in breast tumor cells suggest that these effects are mediated, in large part, through the promotion of autophagic cell death. The residual surviving cell population remains in a senescent, growth arrested state, with minimal recovery of proliferative capacity. It is becoming evident that pathways other than or in addition to apoptosis, including senescence arrest, mitotic catastrophe and autophagy, contribute to loss of self-renewal capacity in tumor cells exposed to chemotherapeutic drugs and ionizing radiation. How and why the cell chooses a particular growth arrest and/or cell death pathway remains a puzzle to be solved.