This review provides an account of why more companies involved in drug discovery fail than succeed at releasing the creative energy of gifted scientists, whose invention of new drugs they rely upon to remain at the forefront of the biopharma industry. Initiatives aimed at improving output of new chemical entities often have the opposite effect from that intended and scientists become demotivated. Those with drive, vision and enthusiasm may move to smaller companies to rediscover the spirit of discovery. Some executives fail to understand the psyche of researchers; an applied understanding of the intrinsic motivation of scientists would improve research performance. Entities that focus on smaller autonomous units and sound ethical values will discover the most innovative and successful new drugs.