Photopharmacology is a growing area of endeavor that employs photoswitchable ligands to allow for light-dependent pharmacological activity. By coupling light to therapeutic action, improved spatial and temporal selectivity can be achieved and subsequently harnessed for new concepts in therapy. Tremendous progress has already been made, with photopharmacological agents now reported against a wide array of target classes and light-dependent results demonstrated in a range of live cell and animal models. Several challenges remain, however, especially in order for photopharmacology to truly impact the clinical management of disease. This Perspective aims to summarize these challenges, particularly with attention to the medicinal chemistry that will be unavoidably required for the further translation of these agents/approaches. By clearly defining challenges for drug hunters, it is hoped that further research into the medicinal chemistry of photopharmacological agents will be stimulated, ultimately enabling full realization of the huge potential for this exciting field.