In the period from January 1981 to December 2010, 1068 small-molecule new chemical entities (NCEs) were introduced, of which ca. 34% are either a natural product or a close analogue. While this metric reflects the impact natural products have played in delivering new chemical starting points (leads) for the pharmaceutical industry, it does not capture the decline this approach has suffered over the last 20 years as the high-throughput screening (HTS) of pure compound libraries has become more popular. An impediment to natural-product drug discovery in the HTS paradigm is the lack of a clear strategy that enables front-loading of an extract or fraction's chemical constituents so that they are compliant with lead- and drug-like chemical space. To address this imbalance, an approach based on lipophilicity, as measured by clog P has been developed that, together with advances being made in isolation and structural elucidation, can afford natural product leads in timelines compatible with pure compound screening.