The introduction of Lipinski's 'Rule of Five' has initiated a profound shift in the thinking paradigm of medicinal chemists. Understanding the difference between biologically active small molecules and drugs became a priority in the drug discovery process, and the importance of addressing pharmacokinetic properties early during lead optimization is a clear result. These concepts of 'drug-likeness' and 'druggability' have been extended to proteins and genes for target identification and selection. How should these concepts be integrated practically into the drug discovery process? This review summarizes the recent advances in the field and examines the usefulness of 'the rules of the game' in practice from a medicinal chemist's standpoint.