The deregulated proteolysis is associated with various diseases in humans. Proteases are commonly regarded as the therapeutic targets. Almost one-third of all proteolytic enzymes in humans are serine proteases. This work provides a brief characteristic of the proteinaceous natural inhibitors, mostly of serine proteases. The examples of some classical and recently identified canonical and noncanonical inhibitors as well as serpins are described. Their actual and potential therapeutic applications are discussed.