The article aimed to give a personal perspective on drug discovery and development. The author has worked both in Big Pharma as a scientist and manager and more recently also in start-up biotech companies. Drug companies have played a major important role in improving population health and will continue to do so. The hurdles and costs for drug development have continuously risen without a parallel enhancement of productivity. There is no single explanation for this and the article outlines success factors and hurdles for effective drug development. Aspects of the external and internal environments that influence Big Pharma productivity is outlined and discussed.