Although medicines have been needed for the entire span of human existence, the age of pharmaceuticals is a relatively recent era. The benefits accompanying the introduction of new medicines meant to combat age-old maladies have dramatically altered public health and society. Herein, we review the history of drug discovery, demonstrating a constant evolution in both the approaches utilized and the outcomes of technological and scientific advances. These innovations have come with a cost as reflected in the ever-increasing amounts of resources to develop a medicine. Indeed, we see the industry, as currently configured, is faced with unprecedented challenges that could soon threaten its very existence.