Lack of efficacy and toxicity are considered to be major reasons for drug failures and pharmacokinetics governs them to a large extent. Compound with favorable pharmacokinetics is more likely to be efficacious and safe. Therefore, the preclinical pharmacokinetic evaluation should be comprehensive enough to ensure that compounds do not fail in the clinic. Preclinical ADME screening facilitates early elimination of weak candidates and directs the entire focus of the drug development program towards fewer potential lead candidates. Hence, it is mandatory that the pre-clinical candidates are subjected to as many possible reality checks. Reliance on in-vitro tests should be minimized because they do not represent the real physiological environment but rather slow down the pace of a drug discovery program. Compounds can be straight away subjected to in-vivo high throughput screens such as cassette dosing, cassette analysis or rapid rat screen etc. Candidates with the desired in-vivo pharmacokinetic profile may be further profiled in-vitro, using assays such as metabolic stability, reaction phenotyping, CYP-450 inhibition and induction, plasma protein binding etc. in human microsomes, human recombinant CYP-450 enzymes and human plasma. This also provides an early indication of whether the compound which worked in animals would work in human as well. In-vitro metabolic stability profile is a qualitative as well as quantitative comparison of metabolism of a compound in human and animal models. It helps in identifying the right model for toxicity studies. Extensive metabolism is generally considered a liability as it limits the systemic exposure and shortens the half-life of a compound. Several strategies such as reduction of lipophilicity, modification and / or blocking of metabolically soft spots and use of enzyme inhibitors; have been developed to combat metabolism. In spite of several concerns, the fact that active metabolites of several marketed drugs have been developed as drugs with better efficacy, safety and pharmacokinetics profile; cannot be denied. Therefore, instead of considering metabolic instability a liability it can be exploited as a tool for discovering better drugs. It is equally important to identify the metabolic pathways of the drug candidates by conducting in-vitro CYP450 reaction phenotyping assays. The identification of drug metabolizing enzymes involved in the major metabolic pathways of a compound helps in predicting the probable drug-drug interactions in human. Compounds with more than one metabolic pathway have less likelihood of clinically significant drug interactions. In-vitro CYP450 inhibition and induction screens are used to evaluate the potential of compound towards drug - drug interactions and the most prone candidates may either be discarded or taken ahead with a caution. It is known that only unbound drug is pharmacologically active and therefore the assessment of bound fraction by the estimation of plasma protein binding of a compound is another important parameter to be explored in...