This mini review describes research on rare and unusual natural and/or semi-synthetic thiirane-containing compounds isolated from plant, fungi, bacteria, and invertebrates. About 40 biologically active epithio metabolites demonstrate confirmed pharmacological activity, including antitumor, antimicrobial, and antibacterial effects. The structures, origin, and biological activities of epithio metabolites are reviewed. Utilizing the computer program PASS, some structure–activity relationship new activities are also predicted, pointing toward possible new applications of these compounds. This article emphasizes the role of natural and/or semi-synthetic thiirane-containing compounds as an important source of drug prototypes and leads for drug discovery.