Covering: Up to 2020Ion channels are a vast super-family of membrane proteins that play critical physiological roles in excitable and non-excitable cells. Their biomedical importance makes them valuable and attractive drug targets for neurological, cardiovascular, gastrointestinal and metabolic diseases, and for cancer therapy and immune modulation. Current therapeutics target only a minor subset of ion channels, leaving a large unexploited space within the ion channel field. Natural products harnessed from the almost unlimited and diverse universe of compounds within the bioenvironment have been used to modulate channels for decades. In this review we highlight the impact made by natural products on ion channel pharmacology, specifically on K+, NaV and CaV channels, and use case studies to describe the development of ion channel-modulating drugs from natural sources for the treatment of pain, heart disease and autoimmune diseases.