 Positron emission tomography (PET) is a widely used imaging technique with many biomedical and drug development applications. The implementation of this technology requires the availability of selective radiotracers with suitable physicochemical characteristics relevant for each target, disease process/pathology, or physiological application. The purpose of the present review was to outline a typical high-level flow scheme for the discovery of PET radiotracers and discuss a variety of methods employed in the field to prosecute the flow scheme steps. In addition, techniques will be described which may be employed to overcome obstacles encountered during the execution of a radiotracer discovery flow scheme when specific challenges are encountered.