The p53 and nuclear factor-kappaB (NF-kappaB) pathways play crucial roles in human cancer, in which inactivation of p53 and hyperactivation of NF-kappaB is a common occurrence. Activation of p53 and inhibition of NF-kappaB promotes apoptosis. Although drugs are being designed to selectively activate p53 or inhibit NF-kappaB, there is no concerted effort yet to deliberately make drugs that can simultaneously do both. Recent results suggest that a surprising selection of small molecules have this desirable dual activity. In this Review we describe the principles behind such dual activities, describe the current candidate molecules and suggest mechanisms and approaches to their further development.