Phytochemicals have long been effective partners in the fight against several diseases, including cancer. Among these, flavonoids are valuable allies for both cancer prevention and therapy since they are known to influence a large panel of tumor-related processes. Particularly, it was revealed that quercetin, one of the most common flavonoids, controls apoptosis and inhibits migration and proliferation, events essential for the development of cancer. In this review, we collected the evidence on the anti-cancer activity of quercetin exploring the network of interactions between this flavonol and the proteins responsible for cancer onset and progression focusing on breast, colorectal and liver cancers, owing to their high worldwide incidence. Moreover, quercetin proved to be also a potentiating agent able to push further the anti-cancer activity of common employed anti-neoplastic agents, thus allowing to lower their dosages and, above all, to sensitize again resistant cancer cells. Finally, novel approaches to delivery systems can enhance quercetin's pharmacokinetics, thus boosting its great potentiality even further. Overall, quercetin has a lot of promise, given its multi-target potentiality; thus, more research is strongly encouraged to properly define its pharmaco-toxicological profile and evaluate its potential for usage in adjuvant and chemoprevention therapy.