This technical article describes the opportunities and risks associated with highly potent active pharmaceutical ingredients (HPAPIs). While these compounds often have properties that enable them to target disease more selectively at significantly lower dosages and with reduced side effects than traditional APIs, they are highly toxic until they reach finished solid or liquid form. Because of the exposure risk, handling of HPAPIs requires facilities with specialized equipment, infrastructure, and expertise from preclinical development through commercial manufacture to protect employees. These are described, as are innovative dosage form technologies that can help reduce occupational risk during the manufacturing process.