Drug design in recent years has attempted to explore new chemical spaces resulting in more complex, larger molecular weight molecules, often with limited water solubility. To deliver molecules with these properties, pharmaceutical scientists have explored many different techniques. An older but time-tested strategy is the design of bioreversible, more water-soluble derivatives of the problematic molecule, or prodrugs. This review explores the use of prodrugs to effect improved oral and parenteral delivery of poorly water-soluble problematic drugs, using both marketed as well as investigational prodrugs as examples. Prodrug interventions should be considered early in the drug discovery paradigm rather than as a technique of last resort. Their importance is supported by the increasing percentage of approved new drug entities that are, in fact, prodrugs.