Improving the efficiency of drug discovery remains a major focus for the pharmaceutical  industry. Toxicity accounts for 90% of withdrawals and major early-stage terminations relate  to suboptimal efficacy and safety. Traditional oral drug space is well defined with respect to physicochemical properties and ADMET risks but increased focus on ligand-lipophilicity efficiency, maximizing enthalpy contributions and new target classes challenge this paradigm. A hybrid space has been identified that combines physical properties and key interactions attributable to drug transporters. A novel algorithm is proposed that incorporates drug–transporter interactions and its utility evaluated against popular ligand efficiency indices. Simply reducing the bulk properties of compounds can exchange one problem for another and creates high-risk areas that challenge the successful delivery from a balanced portfolio.