This special issue of the journal contains contributions from participants of the third La Jolla meeting (The Magic Bullet: A Century Later). The goal of this meeting was twofold: to review approaches to validating molecular imaging agents and to review the progress in advancing the use of molecular imaging from the bench to the bedside, with a special emphasis on how molecular imaging improves patient care and management. Drug development has changed its focus over the years. The original approach depended on direct measurements in patients, whereby, in many cases, the drug was advanced to an NDA based on physiological results (e.g., lowering blood pressure) without identifying a target. Over the past decade, the focus has been on validating a target and choosing the lead compound using combinatorial chemistry and high throughput screening, often at the expense of a focus on the biology of diseases. On the other hand, molecular imaging has been target based since its beginning because of the requirements dictated by external imaging (i.e., a target-to-nontarget ratio). This article explores the possible analogies between current targeted drug development and molecular imaging-targeted probe development with the goal of better defining the path to new molecular imaging probes for the clinic.