The p53 tumor suppressor acts as a transcription factor and has a central function in controlling apoptosis. With p63 and p73 two genes coding for proteins homologous to p53 have been identified. We describe the properties of seven human p63 and p73 proteins as transcriptional activators of p21WAF1/CIP1 expression and apoptotic inducers in direct comparison to p53 in the same assay systems employing DLD-1-tet-off colon cells. Programmed cell death is detected in cells expressing high levels of p53 and p73alpha. Cells overexpressing TAp63alpha, TAp63gamma, TA*p63alpha, TA*p63gamma, DeltaNp63alpha, and DeltaNp63gamma display low or no detectable apoptosis.