Cell proliferation is regulated at two steps: entrance into S phase and entrance into M phase. At the NIH, our research initially focused on the mechanisms that regulate initiation of nuclear DNA replication in metazoan cells from fertilization onward. This work opened a window into the mechanisms that restrict nuclear DNA replication to producing one, but only one, complete copy of the genome each time a cell divides. These studies revealed the mechanisms by which some cells are developmentally programmed to terminally differentiate into nonproliferating polyploid cells. Our research is now focused on the distinctions between stem cells and differentiated cells that would allow us to selectively target genes that are essential in cancer cells to prevent aberrant genome duplication, but that are not essential in 'normal cells'? This research has led to a novel strategy for selectively killing cancer cells, and the identification of new autophagy modulators with therapeutic potential in the treatment of cancer, neurodegenerative diseases, and diseases that elicit an inflammatory response.