Fullerene (C60), a third carbon allotrope, is a classical engineered material with the potential application in biomedicine. One of the biologically most relevant features of C60 is the ability to quench various free radicals, behaving as a "free radical sponge". Conversely, photosensitization of C60 leads to its transition to a long-lived triplet excited state and the subsequent energy or electron transfer to molecular oxygen, yielding highly reactive singlet oxygen (1O2) or superoxide anion (O2-), respectively. These reactive oxygen species (ROS) react with a wide range of biological targets and are known to be involved in both cellular signaling and cell damage. Therefore, the dual property of fullerenes to either quench or generate cell-damaging ROS could be potentially exploited for their development as cytoprotective or cytotoxic anticancer/antimicrobial agents. However, the attempts to that effect have been hampered by the extremely low water solubility of C60, and by the fact that solubilization procedures profoundly influence the ROS-generating/quenching properties of C60, either through chemical modification or through formation of complex nanoscale particles with different photophysical properties. We here analyze the mechanisms and biological consequences of ROS generation/quenching by C60, focusing on the influence that different physico-chemical alterations exert on its ROS-related biological behavior.