Primary sulfonamide and primary sulfamate functional groups feature prominently in the structures of U.S. FDA-approved drugs. However, the natural product chemical space contains few examples of these well-known zinc-binding chemotypes, with just two primary sulfonamide and five primary sulfamate natural products isolated and characterized to date. One of these natural products was isolated from a marine sponge, with the remainder isolated from Streptomyces species. In this review are outlined for the first time the discovery, isolation, striking breadth of bioactivity, and total synthesis (where available) for this rare group of natural products.