Melanoma is the most dangerous type of skin cancer. Despite the rise of public awareness, the incidence rate among the white population has been rising constantly for several decades. Systematic improvement in knowledge about the biology of pigment cells and molecular mechanisms of their neoplastic transformation has enhanced the possibility of melanoma chemoprevention. Hence, chemopreventive agents that prevent, inhibit, or reverse melanoma development are being investigated intensively. Among synthetic compounds, especially well studied are lipid-lowering drugs and cyclooxygenase inhibitors. Substances found in everyday diet, such as genistein, apigenin, quercetin, resveratrol, and curcumin may also have potential chemopreventive qualities. However, studies examining the chemopreventive activity of these compounds have shown widely varying results. Early reports on the possible chemopreventive activity of statins and fibrates were not proved by the results of randomized clinical trials. Similarly, case–control studies examining the influence of NSAIDs on the risk of melanoma do not confirm the antitumor activity of cyclooxygenase inhibitors. Further clinical trials involving carefully selected target populations as well as the identification of specific biomarkers of prognostic and predictive value seem to be essential for the evaluation of the chemopreventive activity of the studied substances.