This review provides a comprehensive critical review of the available literature purporting to assess the toxicity of carbon fullerenes. This is required as prior to the widespread utilization and production of fullerenes, it is necessary to consider the implications of exposure for human health. Traditionally, fullerenes are formed from 60 carbon atoms, arranged in a spherical cage-like structure. However, manipulation of surface chemistry and molecular makeup has created a diverse population of fullerenes, which exhibit drastically different behaviors. The cellular processes that underlie observed fullerene toxicity will be discussed and include oxidative, genotoxic, and cytotoxic responses. The antioxidant/cytoprotective properties of fullerenes (and the attributes responsible for driving these phenomena) have been considered and encourage their utilization within the treatment of oxidant-mediated disease. A number of studies have focused on improving the water solubility of fullerenes in order to enable their exploitation within biological systems. Manipulating fullerene water solubility has included the use of surface modifications, solvents, extended stirring, and mechanical processes. However, the ability of these processes to also impact on fullerene toxicity requires assessment, especially when considering the use of solvents, which particularly appear to enhance fullerene toxicity. A number of the discussed investigations were not conducted to reveal if fullerene behavior was due to their nanoparticle dimensions but instead addressed the biocompatibility and toxicity of fullerenes. The hazards to human health, associated with fullerene exposure, are uncertain at this time, and further investigations are required to decipher such effects before an effective risk assessment can be conducted.