- Lipinski and others, through concepts such as drug-likeness, re-focussed drug discovery back to the principles of medicinal chemistry in the high-throughput era as key to reducing attrition. More recently, the need to go further in defining what makes a good lead has been recognised with the concept of leadlikeness. Leadlikeness implies cut-off values in the physico-chemical profile of chemical libraries such that they have reduced complexity (e.g. MW below <400) and other more restricted properties. We examine these concepts in the context of Virtual (theoretically possible), Tangible (chemically feasible) and Real (physically available) worlds of molecules. In a thought experiment, we take the HTS concept to the extreme: screening an estimated 60 million 'Global Collection' on 5000 targets and realising that perhaps millions of drug candidates might be found that could not possibly be handled in reality. Sampling of the Virtual and Tangible worlds is therefore a necessity. We show that the world of Reals is significantly under-sampled as the MW of compounds increases. This supports the design and screening of 'reduced complexity' (leadlike) compound libraries, preferably with synthetic handles available for rapid chemical iteration and detected as interesting by careful screening or biophysical assays.