While molecules that promote the growth of animal cells have been identified, it remains unclear how such signals are orchestrated to determine a characteristic target size for different cell types. It is increasingly clear that cell size is determined by size checkpoints—mechanisms that restrict the cell cycle progression of cells that are smaller than their target size. Previously, we described a p38 MAPK-dependent cell size checkpoint mechanism whereby p38 is selectively activated and prevents cell cycle progression in cells that are smaller than a given target size. In this study, we show that the specific target size required for inactivation of p38 and transition through the cell cycle is determined by CDK4 activity. Our data suggest a model whereby p38 and CDK4 cooperate analogously to the function of a thermostat: while p38 senses irregularities in size, CDK4 corresponds to the thermostat dial that sets the target size. Display omitted •Homeostatic mechanisms maintain cells at a given target size•p38 MAPK promotes growth of cells that are smaller than the critical target size•CDK4 determines the target size by regulating both the duration and rate of cell growth Tan et al. study homeostatic mechanisms that maintain animal cells at their appropriate target size. They find that p38 is part of a sensing mechanism that identifies inappropriately sized cells, while CDK4 is analogous to a thermostat dial that sets the target size set point referenced by p38.