The importance of nitriles as a key class of chemicals with applications across the sciences is widely appreciated. The natural world is an underappreciated source of chemically diverse nitriles. With this in mind, this review describes novel nitrile-containing molecules isolated from natural sources from 1998 to 2021, as well as a discussion of the biological activity of these compounds. This study gathers 192 molecules from varied origins across the plant, animal, and microbial worlds. Their biological activity is extremely diverse, with many potential medicinal applications.