The prediction of the structure of metabolites based solely on consideration of the chemical structure of the parent can provide value during drug discovery, including lead optimisation and development. Since metabolism frequently has a direct influence on pharmacological activity profiles, toxicity and idiosyncratic drug reactions, consideration of metabolism has become increasingly recognised as vital in the optimisation of lead compounds selected for development. By whatever means prediction is achieved it will always be limited by the extent of existing knowledge. The challenge is to find the means of capturing and accessing knowledge and complementing this with tools that can that can take account of specific structural and physicochemical properties for compounds of interest. Two types of expert systems can be defined, the first being human experts with access to knowledge databases and the second in silico prediction systems. The tools available to a human expert and the approaches to their use are discussed and illustrated. The development of in silico systems and the existing products are reviewed. In silico systems are still at an early stage of development and there is considerable scope for their further enhancement. However it is also the case that some human expertise should be included to modulate outputs. One element of metabolism is the ability to predict potential for formation of reactive intermediates, which may contribute to toxicity or other adverse effects. This issue is more directed to providing alerts rather than predicting the structures of metabolites and in silico systems with the capability of recognising structural elements according to defined rules could provide the ideal vehicle to make predictive assessments. Examples are described of how structural alerts can be identified from existing knowledge. Input from the above initiatives could be at any stage of the drug discovery process since it is a purely theoretical exercise. There could be value in early implementation since this will expand the chemical space of candidates based on metabolic considerations and will therefore provide the opportunity to include compounds with a broader range of metabolic stability. The strategy adopted will clearly depend on what is most suitable to each specific company based on its organisation.