Lycopodium species produce a number of structurally diverse alkaloids, which often possess unusual skeletons, and many of them continue to be of interest from the biogenetic and biological points of view, as well as providing challenging targets for total synthesis. There are over 500 species in the genus Lycopodium (family Lycopodiaceae), but the alkaloid content has been studied in fewer than 40 species (1-5). Most of the species are low, evergreen, coarsely moss-like plants, which are commonly known as club mosses. They are non-flowering plants which reproduce by means of spores rather than seeds. In many species, the spore-bearing bodies, known as strobili, appear as club-shaped growths at the tips of the moss like branches, hence the name club mosses. The taxonomy of the genus and the family is still in a state of flux. Some botanists have subdivided the genus into four genera (Lycopodium, Diphasiastrum, Lycopodiella, and Huperzia), and some have placed Huperzia in a separate family (6,7 ). We prefer to retain the single genus name, since this allows us to use a name which is familiar to most and typifies plants that can be easily recognized as being closely related. Huperzine A (1) has been shown to be a potent, reversible inhibitor of acetylcholine esterase and shows promise in the treatment of Alzheimer's disease and myasthenia gravis (8-10). This alkaloid has provided the focus for a good portion of the synthetic work in the period under review. The biosynthesis of the alkaloids is still not completely understood, and only limited biosynthetic studies have been reported. Plants of the genus Lycopodium have not been cultivated, and labeling experiments must be carried out in the field. Because the club mosses often are not easily accessible, very few feeding studies have been conducted. This is an area where plant tissue culture may prove extremely useful in future biosynthetic studies. There are some reviews of the chemistry of Lycopodium alkaloids (1-5), and of the biology and chemistry of huperzine A (1) (8-10). Since the last review by Ayer in Volume 45 (4) of this treatise, a number of new Lycopodium alkaloids have been discovered. As a result, the number of known Lycopodium alkaloids has grown markedly in recent years to a present count of ca. 200. These alkaloids, isolated chiefly by Manske and Ayer et al., are classified into different frameworks of C16N, C16N2, and C27N3 types (1-4 ). These unusual ring systems have attracted great interest as challenging targets for total synthesis or biosynthetic studies. This chapter covers the reports on Lycopodium alkaloids that have been published between 1993 to 2003, and provides an update of the previous review by Ayer in 1994 (4). The natural Lycopodium alkaloids published between 1993 to 2003 (compounds 1-82) are listed in Table I. Classification of the alkaloids basically follows that of the previous reviews (1-4), but sections on the newly found skeletons have been added. This review describes the recent studies on Lycopodium alkaloids isolated from the genus Lycopodium and Huperzia, the proposed biogenetic pathway, and the syntheses of Lycopodium alkaloids based on these biogenetic proposals. In section II, all of the Lycopodium alkaloids isolated so far, and including our recent work, are surveyed, while sections III and IV mainly deal with the biogenetic pathways and the total syntheses of the Lycopodium alkaloids, respectively. In sections V, VI, and VII, pharmacology, total synthesis, and SAR studies, respectively of huperzine A (1) are briefly surveyed. © 2005 Elsevier Inc. All rights reserved.