Secondary pharmacodynamic studies of new chemical entities (NCEs) play a critical role in support of efficient drug discovery. In an era in which speed and efficiency are the norm for pharmaceutical discovery, the need to identify NCEs with greater patient tolerability continues to increase. Early use of secondary pharmacodynamic models (in vivo and in vitro) provides the foundation for critical, early decisions regarding lead molecules. Scientifically robust, non-GLP (good laboratory practices) secondary pharmacodynamic studies can eliminate compounds or structural series with undesirable profiles early, and may prove useful in defining structure-activity relationships (SARs) with regards to off-target effects.