Cancer is a major public health problem worldwide. Over two-thirds of cancer-related deaths could most probably be prevented through lifestyle modification, particularly through dietary means. Proanthocyanidins (PAs), the most abundant polyphenolic substances after lignin in the plant kingdom, have been widely investigated for their chemopreventive potential. The PAs literature has, however, been mostly concerned with positive cardiovascular activities, and recent reviews about cancer chemoprevention are scarce. The present review highlights a series of in vitro and in vivo studies indicating ( 1 ) that PAs can act as anticarcinogenic agents through their antioxidant, apoptosis-inducing, immuno-modulating, and/or enzyme modulating properties, effects on epigenetics; and ( 2 ) that PAs could be particularly safe dietary compounds. These convergent data encourage further research to better understand the many aspects of cancer chemoprevention by PAs.