Many original research articles have been published that describe findings and outline areas for the development of kappa-opioid agonists (KOAs) as novel drugs; however, a single review article that summarizes the broad potential for KOAs in drug development does not exist. It is well-established that KOAs demonstrate efficacy in pain attenuation; however, KOAs also have proven to be beneficial in treating a variety of novel but often overlapping conditions including cardiovascular disease, pruritus, nausea, inflammatory diseases, spinal anesthesia, stroke, hypoxic pulmonary hypertension, multiple sclerosis, addiction, and post-traumatic cartilage degeneration. This article summarizes key findings of KOAs and discusses the untapped therapeutic potential of KOAs in the treatment of many human diseases.