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Piericidins are a family of α-pyridone antibiotics with fascinating biological activity produced by actinomycetes, derived from land soil, insect or marine samples. There are 39 natural piericidins reported before 2016, and most of them are obtained from soil actinomycetes. However, marine-derived Streptomyces isolates have been showed great importance to produce piericidins with new structures in recent 5 years. This review covers the 40 natural piericidins reported after 2016, together with their obvious cytotoxic activities against cancer cell lines. Their structure–activity relationships are also discussed briefly. The anti-tumor potential, especially as lead compounds for anti-renal cell carcinoma agents, is of great concern recently. This review helps to provide comprehensive chemical information and new insights into the antitumor potential of piericidins. more...