Malaria represents a significant health issue, and novel and effective drugs are needed to address parasite resistance that has emerged to the current drug arsenal. Antimalarial drug discovery has historically benefited from a whole-cell (phenotypic) screening approach to identify lead molecules. This approach has been utilized by several groups to optimize weakly active antimalarial pharmacophores, such as the quinolone scaffold, to yield potent and highly efficacious compounds that are now poised to enter clinical trials. More recently, GNF/Novartis, GSK, and others have employed the same approach in high-throughput screening (HTS) of large compound libraries to find novel scaffolds that have also been optimized to clinical candidates by GNF/Novartis. This perspective outlines some of the inherent challenges in cell-based medicinal chemistry optimization, including optimization of oral exposure and hERG activity.