DYRK1A is a member of the dual-specificity tyrosine-phosphorylation-reg-ulated protein kinase family and is implicated in Down’s syndrome. Here, we identify the cysteine aspartyl protease caspase9, a critical component of the intrinsic apoptotic pathway, as a substrate of DYRK1A. Depletion of DYRK1A from human cells by short interfering RNA inhibits the basal phosphorylation of caspase9 at an inhibitory site, Thr125.