Understanding the development of a scientific approach is a valuable exercise in gauging the potential directions the process could take in the future. The relatively short history of applying computational methods to absorption, distribution, metabolism and excretion (ADME) can be split into defined periods. The first began in the 1960s and continued through the 1970s with the work of Corwin Hansch et al. Their models utilized small sets of in vivo ADME data. The second era from the 1980s through 1990s witnessed the widespread incorporation of in vitro approaches as surrogates of in vivo ADME studies. These approaches fostered the initiation and increase in interpretable computational ADME models available in the literature. The third era is the present were there are many literature data sets derived from in vitro data for absorption, drug-drug interactions (DDI), drug transporters and efflux pumps [P-glycoprotein (P-gp), MRP], intrinsic clearance and brain penetration, which can theoretically be used to predict the situation in vivo in humans. Combinatorial synthesis, high throughput screening and computational approaches have emerged as a result of continual pressure on pharmaceutical companies to accelerate drug discovery while decreasing drug development costs. The goal has become to reduce the drop-out rate of drug candidates in the latter, most expensive stages of drug development. This is accomplished by increasing the failure rate of candidate compounds in the preclinical stages and increasing the speed of nomination of likely clinical candidates. The industry now understands the reasons for clinical failure other than efficacy are mainly related to pharmacokinetics and toxicity. The late 1990s saw significant company investment in ADME and drug safety departments to assess properties such as metabolic stability, cytochrome P-450 inhibition, absorption and genotoxicity earlier in the drug discovery paradigm. The next logical step in this process is the evaluation of higher throughput data to determine if computational (in silico) models can be constructed and validated from it. Such models would allow an exponential increase in the number of compounds screened virtually for ADME parameters. A number of researchers have started to utilize in silico, in vitro and in vivo approaches in parallel to address intestinal permeability and cytochrome P-450-mediated DDI. This review will assess how computational approaches for ADME parameters have evolved and how they are likely to progress.