Hit selection and lead generation are crucial for the success of the resource-demanding lead-optimization phase in drug discovery, and represent a major research area of medicinal chemistry today. Ligand-binding efficiency, ligand complexity, ligand-target profile complementarity and chemical tractability are important parameters in hit selection. As synthesis and assay throughput improve, a large number of analogs based on the same scaffold can be rapidly synthesized and tested. Consequently, more chemistry resources could be devoted to scaffold modifications to expand the candidate pool in lead generation. Most recently discovered druggable targets are promiscuous toward lipophilic ligands, and the hydrophobic portions of hit compounds should be preferentially modified in analog and scaffold design.