Drug development today needs to balance agility, speed and risk in defining the probability of success for molecules, mechanisms and therapeutic concepts. New techniques in functional magnetic resonance imaging (fMRI) promise to be part of a sequence that could transform drug development for disorders of the central nervous system (CNS) by examining brain systems and their functional activation dynamically. The brain is complex and multiple transmitters and intersecting brain circuits are implicated in many CNS disorders. CNS therapeutics are designed against specific CNS targets, many of which are unprecedented. The challenge is to reveal the functional consequences of these interactions to assess therapeutic potential. fMRI can help optimize CNS drug discovery by providing a key metric that can increase confidence in early decision-making, thereby improving success rates and reducing risk, development times and costs of drug development.