The cyclin-dependent kinase inhibitor p27(Kip1) is a critical cell cycle regulator, and decreased p27 levels are associated with poor prognosis in a variety of malignancies, including multiple myeloma. Decreased p27Kip1 expression occurs primarily through enhanced proteolysis by up-regulation of the SCF(Skp2)-Cks1 E3 complex responsible for p27 ubiquitination. We hypothesize that, unlike proteasome inhibition, targeting SCF(Skp2) will provide a more specific means of activating programmed cell death without induction of anti-apoptotic pathways. Based on encouraging preliminary data, we propose additional studies using genetic and pharmacologic approaches to validate SCF(Skp2 ) as a novel, rational target for myeloma therapy.