THE stress-activated protein kinases (SAPKs), which are identical to the c-Jun amino-terminal kinases (JNKs), are activated in response to a variety of cellular stresses, including DNA damage, heat shock or tumour-necrosis factor-alpha(1,2). SAPK, a subfamily of the mitogen-activated protein (MAP) kinases, is a major protein kinase that phosphorylates c-Jun and other transcription factors(2-5). SAPK phosphorylation of transcription factors is important in stress-activated signalling cascades(1-6). Here we report that the protein p21(WAF1/CIP1/Sdi1), a DNA-damage-inducible cell-cycle inhibitor(7-10), acts as an inhibitor of the SAPK group of mammalian MAP kinases. This highlights a new biochemical activity of p21, which may provide the first evidence for a non-enzymatic inhibitory protein for SAPK. We suggest that p21, by inhibiting SAPK, may participate in regulating signalling cascades that are activated by cellular stresses such as DNA damage.