Its outstanding ability to generate singlet oxygen or reactive oxygen species upon irradiation with light makes hypericin one of the most powerful photosensitizers to be found in nature. The most important fields of application of hypericin seem presently to be its use as a photosensitizing anti-viral agent to destroy virus particles in blood preparations, to sensitize the destruction of superficial tumors, and its use as a diagnostic tool for fluorescence detection of malignant tissue. Despite of all of its benefits and its strong photosensitizing ability, the application of hypericin in photodynamic therapy (PDT) suffers from three main disadvantages: cost expensive isolation, limited solubility under physiological conditions, long wavelength absorption maximum outside the optimum wavelength range for a photosensitizer. Thus, over the last decade several efforts have been undertaken to synthesize new hypericin derivatives with increased solubility, bathochromically shifted long wavelength absorption band, enhanced photosensitizing potential, and applicability in a more widespread field (second generation hypericin based photosensitizers). The objective of this review is to discuss the investigations undertaken in the development of second generation hypericin based photosensitizers. The focus will be on the synthesis aspects of such derivatives as well as on their photochemical properties, their advantages, and disadvantages. Several of these novel synthetic hypericin derivatives have already been tested in vitro and/or in vivo. Accordingly, also a summary of the corresponding results will be presented.