Caspases, or cysteinyl-aspartate specific proteases, are major contributing enzymes in inflammation. Caspases are highly specific cysteine proteases closely involved in inflammatory responses that are associated with programmed cell death, or apoptosis. Inappropriate regulation of cell death, therefore, substantially results in a wide array of diseases including, but not limiting to, neurodegenerative disorders, ischemic disorders, and cancer. The key molecular genes that control cell death are those cell death effectors (pro-apoptosis) of the caspase family, on one hand, and the cell death inhibitors (anti-apoptosis) of the Bcl-2 family, on the other hand. This unequivocal and unprecedented equilibrium between caspases and Bcl-2-related molecules essentially controls cells’ final demise. Caspases and related proteases are potential therapeutic targets in a variety of acute and chronic diseases. Current design of biologically active molecules in recent technology is dependent on DNA-based scanning of the genome to engineer a variety of molecules such as apoptosis inhibitors, caspase regulators and caspase activators, and cytokines involved in caspase signaling. This synopsis aims to review relevant patents and to unravel the discovery of small-molecule caspase protease inhibitors and their clinical ramifications, and further sheds light on recent experimental and clinical trials, emphasizing a small molecule dubbed 3-[2-[(2- tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid (IDN- 6556/PF-03491390). Current opinion on investigational drugs targeting caspases and caspase-like proteases bears the significance of understanding the mechanisms of alleviating inflammatory-related acute and chronic conditions and their biomedical applications and repercussions.