p21^WAF1/CIP1 is a cyclin-dependent kinase inhibitor whose expression in mammalian tissues is highly induced in response to stress as well as during normal development and differentiation. Induction of p21^WAF1/CIP1 in response to DNA damage occurs through a transcriptional mechanism that is dependent on the activation of the tumor suppressor protein p53. Recent evidence indicates that p21^WAF1/CIP1 can also be induced independent of p53, but the signal transduction mechanisms involved in regulating p21^WAF1/CIP1 expression in these situations have not been elucidated. In this study, we have addressed the role of the mitogen-activated protein kinase signaling pathway in the induction of p21^WAF1/CIP1 in response to growth factor treatment. Using an experimental approach involving cotransfection of a p21^WAF1/CIP1 promoter-luciferase construct with a variety of plasmids expressing dominant positive or dominant negative mutant proteins involved in this signaling pathway, we provide evidence to support a role for mitogen-activated protein kinase in the transcriptional activation of p21^WAF1/CIP1 by growth factor stimulation.