For the past decade the pharmaceutical industry has experienced a steady decline in productivity and a striking observation is that the decline coincided with the introduction of target-based drug discovery. The target-based approach can very effectively develop novel treatments for a validated target, but the process of target validation is complex and associated with a high degree of uncertainty. The purpose of this paper is to analyse these aspects in detail to determine if weaknesses in this part of the drug discovery path might explain why this paradigm has not resulted in increased productivity over the traditional in vivo approach, considering its superiority in screening capacity and its ability to define rational drug discovery programs.