Physicochemical properties underlie all aspects of drug action and are critical for solubility, permeability and successful formulation. Specific physicochemical properties shown to be relevant to oral drugs are size, lipophilicity, ionisation, hydrogen bonding, polarity, aromaticity and shape. The rule of 5 (Ro5) and subsequent studies have raised awareness of the importance of compound quality amongst bioactive molecules. Lipophilicity, probably the most important physical property of oral drugs, has on average changed little over time in oral drugs, until increases in drugs published after 1990. In contrast other molecular properties such as average size have increased significantly. Factors influencing property inflation include the targets pursued, where antivirals frequently violate the Ro5, risk/benefit considerations, and variable drug discovery practices. The compounds published in patents from the pharmaceutical industry are on average larger, more lipophilic and less complex than marketed oral drugs. The variation between individual companies' patented compounds is due to different practices and not to the targets pursued. Overall, there is demonstrable physical property attrition in moving from patents to candidate drugs to marketed drugs. The pharmaceutical industry's recent poor productivity has been due, in part, to progression of molecules that are unable to unambiguously test clinical efficacy, and attrition can therefore be improved by ensuring candidate drug quality is ‘fit for purpose.’ The combined ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of many marketed drugs are optimised relative to other molecules acting at the same target. Application of LLE in optimisation can help identify improved leads, even with challenging targets that seem to require lipophilic ligands. Because of their targets, some projects may need to pursue ‘beyond Ro5’ physicochemical space; such projects will require non-standard lead generation and optimisation and should not dominate in a well-balanced portfolio. Compound quality is controllable by lead selection and optimisation and should not be a cause of clinical failure.