How mitogens reduce the abundance of the cell cycle inhibitor p27^Kip1 is an important question, and regulation of p27^Kip1 translation and turnover has been described.  Here we show that platelet-derived growth factor (PDGF) reduces the activity of the p27^Kip1 promoter and the abundance of the p27^Kip1 transcript in density-arrested mouse fibroblasts.  Inhibition of p27^Kip1 gene expression by PDGF required protein synthesis and histone deacetylase activity but not Akt or ERK activity.  PDGF increased the expression of c-Myc in the absence but not presence of a histone deacetylase inhibitor, and c-Myc inhibited p27^Kip1 promoter activity when ectopically expressed in fibroblasts.  c-Myc targeted the same region of the p27^Kip1 promoter as did PDGF (deletion analysis) and interacted with this region in vivo (chromatin immunoprecipitation assay).  Collectively, these findings suggest that c-Myc mediates the inhibitory effects of PDGF on the p27^Kip1 promoter.  We also demonstrate reductions in p27^Kip1 mRNA abundance in primary splenocytes exposed to concanavalin A and in T cells exposed to interleukin-2 (IL-2).  In contrast to PDGF in fibroblasts, IL-2 required Akt activity for maximal reductions in p27^Kip1 promoter activity and mRNA abundance in T cells.  Thus, mitogens repress p27^Kip1 gene transcription in multiple systems and by multiple mechanisms.