Abstract: Mammals must regulate the proliferation of stem, progenitor and differentiated cells to build, maintain, and repair tissues. Control of cell-cycle entry and exit has been conceptualized by the restriction point, a time when cells escape the need for mitogens to complete the cell cycle. Our single-cell microscopy studies discovered instead two parallel and partially redundant pathways to enter the cell cycle out of quiescence and three pathways out of mitosis. In lieu of a sharp restriction point, we find a progressive stabilization of both increasing CDK4/6 and CDK2 activities when tested by mitogen removal or stress, a stabilization that ends with an irreversible commitment point driven by multiple positive feedbacks. I will delineate core principles, molecular mechanisms and timing of this fundamental cell-fate commitment whose abnormal regulation is a main cause for cancer.