The failure rate in the latter stages of the drug discovery pipeline is high, often resulting from a lack of drug efficacy in vivo, newly identified safety risks, or incorrect populations enrolled in the clinical trials. The attrition rate in Phase II is particularly acute at approximately 70%, which results mainly from a lack of effective target validation earlier in the drug discovery process. It has been estimated that more robust target validation and proof-of-concept studies earlier in the process would increase the probability of a successful Phase II trial to approximately 50%, and could reduce the cost of a new molecular entity by 30%. Both chemical and genetic techniques play an important role in target validation. Knock-down/knockin, gene mutations, and siRNA/shRNA are routinely used to modulate the expression of, or to modify the function of, a specific gene in cells, linking the target with an observed phenotype. However, the effect of knocking-down protein is complex, affects all functions of a multidomain protein, and can lead to the activation of compensatory pathways in cells. Chemical tools provide temporal control of protein function, allowing phenotypic studies on a native, and non-engineered system. Small molecules can also allow the function of an individual protein domain to be removed, while leaving scaffolding roles and the function of other domains unaffected. Despite these advantages, the development of small molecules with the exquisite target selectivity required to confidently link target inhibition to phenotype is challenging and time consuming.