Intracellular localization plays an important role in the functional regulation of the cyclin-dependent kinase inhibitor p21. While nuclear functions have been linked to the tumor suppressor activity of p21, cytoplasmatic functions are oncogenic. We have recently shown that Ser153 phosphorylation of p21 by PKC contributes to its cytoplasmatic accumulation, and that this phosphorylation is inhibited by Ca(2+)-dependent calmodulin binding to the C-terminal region of p21. Consequently, PKC and calmodulin/Ca(2+) play diverging roles in the regulation of p21 intracellular localization. Other kinases such as AKT and MIRK/dyrk1B also phosphorylate p21 near the nuclear localization signal, thus inhibiting its nuclear accumulation. We discuss here the effects of such phosphorylations on p21 functionality, as well as its relevance to cell cycle progression and differentiation.