Although deaths and life-threatening adverse drug reactions (ADRs) in Phase I clinical trials are extremely rare, less severe ADRs occur with an incidence of over 13%. Of the candidate drugs (CDs) that fail prior to marketing, it is generally acknowledged that about 1 in 5 do so because of ADRs in the clinic. Once new chemical entities (NCEs) are on the market, ADRs are estimated to be the fourth leading cause of death in the USA. These various statistics indicate that there is room for improvement in preclinical safety assessment, and a smarter approach to safety pharmacology (SP) can contribute to this. Rather than 'bundling' the SP studies together just prior to Phase I trials, a step-wise, streamlined approach can be adopted throughout the drug discovery process. In this way, the SP information can contribute to making informed judgements at each milestone throughout the preclinical drug discovery process: (i) to assist in series and compound selection; (ii) to assess potential risk of failure in the clinic due to ADRs; (iii) to predict potential ADRs that the clinical pharmacologists can focus on; (iv) to define a therapeutic window for acute dosing in humans. To achieve these objectives, the SP tests need to be carefully selected, adequately validated in-house, and be robust and reliable. To achieve (ii) above, outcome criteria have to be set which, for each test (in vitro and in vivo), take into account acceptable safety margins for the particular therapeutic target. Thus, highly sensitive and predictive SP tests positioned strategically and as early as possible should contribute to reducing attrition during clinical development and ultimately to marketing safer medicines more rapidly.