This chapter reviews a non-exhaustive number of close to 200 natural products and lead compounds with isoquinoline scaffolds used in drug development. Two classes of small-molecule drug candidates are discussed: firstly, those derived from natural products and, secondly, those that are chemically engineered based on structure–activity relationships (SAR). Eleven classes of natural products and the class of synthetic mono- to polysubstituted isoquinolines are presented. The application of isoquinoline moieties covers therapeutic areas such as HCV, ocular diseases, cancer, inflammatory diseases, metabolic disorders, and diabetes mellitus. The results of this review suggest that few isoquinoline scaffolds succeed in entering the commercial phase as drugs, but that academia and industry make intensive experimental efforts to find new therapeutic isoquinoline derivatives. Isoquinolines can be exploited as multi-target drugs and are therefore a constituent of privileged scaffolds.