For a few years, in vitro models have been used as part of high-throughput screening (HTS) programs to characterize metabolic stability, drug permeability and drug solubility. This has allowed the rapid selection of lead candidates based not only on pharmacological endpoints but also on biopharmaceutical specifications. What has now become clear is that the huge amount of data produced to sort series of compounds has a limited predictive value when used to predict human pharmacokinetic parameters. More complex in vitro tests together with some simple in vivo tests used as validation steps have been developed in order to provide absolute data that may be used as a complement to lead selection providing reliable predictions not only of human pharmacokinetics but also of potential drug-drug interactions. These models may be used as part of selective drug screening (SDS) programs. Further advances in analytical and in vitro techniques will see some of these models shifting from SDS to HTS programs putting the emphasis on the use of expert systems and physiologically based pharmacokinetic models (PBPK) to provide meaningful endpoint data.