When genome-wide expression profiles of tumors are compared to those of normal tissues, the most recurring transcriptional pattern is characterized by an increased expression of cell-cycle and proliferation-associated genes, collectively referred to as the 'proliferation cluster'. Tumors with increased expression of the proliferation cluster are frequently associated with augmented proliferation rate, chromosomal instability and metastasis as well as with poor prognosis. Recent in vitro and in vivo data establish a link between the tumor suppressor p53 and the proliferation cluster, implicating loss of p53 activity as the major event responsible for elevated expression of the proliferation cluster in tumors. Moreover, a complex regulatory network, which links p53 with the transcription factors that govern the expression of the proliferation cluster genes, is being gradually elucidated.