Lycopodium is a genus of the family Pteridophytes, which is widely distributed in temperate and tropical climates and tropical mountains. Plants of genus Lycopodium are ancient medicinal plants which have been used in different traditional medicinal system to treat many diseases, mainly focus on central nervous system and inflammation-related diseases. Rigorous pharmacological and clinical studies conducted in recent decades have demonstrated their special efficacy in the treatment of Alzheimer's disease (AD). Furthermore, secondary metabolites and extracts from these plants have been proven to possess neuroprotective, anti-tumor, anti-inflammatory, anti-microbial, and antiviral effects, which supports most of traditional medicinal uses of Lycopodium plants. To date, a total of 508 secondary metabolites have been reported from the 46 species belonging to genus Lycopodium. Among those metabolites, Lycopodium alkaloids and serratene triterpenoids represent two major classes of bioactive ingredients. Notably, huperzine A, a Lycopodium alkaloid originally isolated from L. serratum, was licensed in China as a drug for the treatment of AD and in the United States as a dietary supplement. Besides, serratane-type triterpenoids may be potential candidates for the development of anticancer drugs. This review covers the literatures available from 1947 to 2020 and mainly discusses knowledge on ethnopharmacology, secondary metabolites, pharmacological activities, clinical trials, toxicology, and quality control of Lycopodium species. In addition, the present review also draws attention to the gaps that still exist in the scientific studies on Lycopodium plants, which would accelerate the contemporary development of this traditional medicinal plant. [GRAPHICS] .