Drug discovery and development is a complex and lengthy enterprise that suffers from high rates of candidate attrition at all stages of the process. The physical, biological, and toxicological properties of a drug candidate are inextricably linked to its structure, and once a molecule has been synthesized, all subsequent studies along the development path are focused only on assessing and understanding its properties in greater detail. Unfortunately, a full prediction of the biological properties of a molecule from an analysis of its 2- or 3-dimensional structure is currently beyond our expertise. This backdrop mandates that considerable care be taken at the design stage if a molecule is to be successful in testing a mechanistic concept underlying a disease process and to progress into late stage clinical trials and, ultimately, marketing approval. While there are multiple potential causes of candidate attrition, an introspective analysis of drug design practices over the past decade has focused attention on the perception that contemporary molecules are unnecessarily obese, burdened by high molecular weight and excessive lipophilicity. This practice is believed to have its roots in the singular pursuit of enhancing potency during lead optimization rather than adopting a more holistic approach to drug design that gives broader consideration to how structural features affect developability properties. In an effort to provide the medicinal chemistry community with practical guideposts to enhancing compound quality in the drug design phase and which can readily be applied, a series of efficiency indices have been proposed that attempt to define aspects of compound quality in the context of a series of physicochemical parameters. Of these metrics, lipophilic ligand efficiency (LLE or LipE), which provides an index of the dependence of the potency of a molecule on its intrinsic lipophilicity, has been characterized as the most robust metric that has potential for broad-based application. In this review, after describing the background literature behind the derivation of efficiency metrics and approaches to assessing compound aesthetics, synopses of some recent practical application in lead optimization campaigns are presented. However, molecules that fall into space beyond that associated with traditional drug-like properties are an important part of the current and future landscape, exemplified by the summary of direct acting hepatitis C virus NS3 and NS5A inhibitors that have transformed clinical therapy for this chronic disease. While drug development in nontraditional drug-like space is more challenging and the rules for compound quality will be different with much still to be understood, careful and disciplined drug design practices will be an essential element of success.