The genus Hypericum (Hypericaceae) consists of 484 species from 36 sections with worldwide distribution in different areas. Turkey is considered as hot spot for diversity of Hypericum genus. Despite numerous publications, Hypericum species still attracted considerable scientific interest due to pharmaceutically relevant secondary metabolites: naphthodianthrones, acylphloroglucinol derivatives, phenolic acids, flavonoid glycosides, biflavonoids, and some other valuable constituents. Phytochemical investigations carried out on different Hypericum species provided highly heterogeneous results. The content of bioactive compounds varies significantly due to many internal and external factors, including plant organs, phenological stage, genetic profile, environmental abiotic and biotic factors, such as growing site, light, temperature, radiation, soil drought and salinity, pathogens, and herbivores attack. The variations in content of bioactive compounds in plants are regarded as the main problem in the standardization of Hypericum-derived pharmaceuticals and dietary supplements. The review discusses the main factors contributing to the variations of bioactive compounds and what kind of modulations can increase quality of Hypericum raw material.