Recent studies are beginning to disclose a signaling network involved in regulating cell size. Although many links and effectors are still unknown, central components of this network include the mammalian target of rapamycin (mTOR) and its downstream effectors - the ribosomal protein S6 kinase (S6K) and the translational repressor eukaryotic initiation factor 4E-binding protein. Until recently, the role of S6K and its many substrates in cell-size control remained obscure; however, a knockin mouse carrying mutations at all phosphorylation sites in the primary S6K substrate, ribosomal protein S6 (rpS6), has provided insight into the physiological role of this protein phosphorylation event. In addition to its role in glucose homeostasis in the whole mouse, phosphorylation of rpS6 is essential for regulating the size of at least some cell types, but is dispensable for translational control of mRNAs with a 5' terminal oligopyrimidine tract (TOP mRNAs) - its previously assigned targets. It therefore seems that establishing the function of the phosphorylation of other effectors of mTOR or S6K will inevitably require genetic manipulation of the respective sites within these targets.