Genetic intervention in cell-cycle regulation is a promising strategy to obtain mammalian cell culture proliferation in the absence of exogenous growth factors. In order to gain insights into this approach, known interactions among the four proteins cyclin E, cdk2, the retinoblastoma gene product (RB), and the transcription factor E2F, all centrally involved in control of the G1/S transition of the eucaryotic cell cycle, guided the formulation of kinetics in intracellular mass balances on these components. Stable oscillatory solutions of these equations, which include the diluting effects of cell volume increase and a resulting special boundary condition, correspond to cell proliferation. The model simulates the qualitative consequences on cell cycle regulation of overexpression of cyclin E, E2F, and of RB deregulation in agreement with experiment. Bifurcation analysis of the model suggests strategies for rational manipulation of the cell cycle.