Over the last 15 years, the annual number of approved new drugs has been declining dramatically. Meanwhile, the pharmaceutical industry, as well as academic and government researchers, have dramatically increased the amount of money spent on drug discovery and development. Why is the large increase in funding not translating into new medicines?One explanation for this failure is that we are running out of tractable drug targets.Drugs function by interacting with, i.e. attaching to, specific proteins within the body, which are called “drug targets.” However, only 2% of the proteins found in humans have been targeted with drugs.Most of the remaining proteins are considered “undruggable,” meaning it is difficult or perhaps impossible to make drugs that interact with these proteins.If this is true, then we are really running out of drug targets—and therefore running out of new drugs.And this could be the explanation behind the challenging state of drug discovery, the decline of the pharmaceutical industry and the paucity of new medicines.Proteins are large molecules with specific three-dimensional shapes. The more tractable proteins have large crevices, or pockets, on their surfaces. Here is where small molecule drugs can snugly fit. And when this happens, the drug alters the function of the protein. Which, in turn, can lead to a change in the course of a patient’s disease.Undruggable proteins generally don’t have large pockets on their surfaces. Instead, from the perspective of a small molecule drug, they look relatively smooth and featureless.The majority of proteins are considered undruggable. These proteins control nearly every disease process, from many types of cancer to neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Lou Gehrig’s, to many other diseases.One approach for tackling these proteins is to create huge collections of candidate drugs (thousands or even millions of them) and to use advanced robotic systems to rapidly test for any that affect undruggable proteins.A second approach is to design drugs using sophisticated computer algorithms—by trying to find a way to get a foothold on the surface of these proteins.Another exciting strategy is to build larger molecules that have a better ability to interact with the undruggable proteins, and then to solve the issue of how to deliver these larger molecules into a target tissue, such as a tumor.All three are currently areas of active research—but one may hold the key to solving the mystery of the undruggable proteins.