Graphene based nanomaterials possess remarkable physiochemical properties suitable for diverse applications in electronics, telecommunications, energy and healthcare. The human and environmental exposure to graphene-based nanomaterials is increasing due to advancements in the synthesis, characterization and large-scale production of graphene and the subsequent development of graphene based biomedical and consumer products. A large number of in vitro and in vivo toxicological studies have evaluated the interactions of graphene-based nanomaterials with various living systems such as microbes, mammalian cells, and animal models. A significant number of studies have examined the short- and long-term in vivo toxicity and biodistribution of graphene synthesized by variety of methods and starting materials. A key focus of these examinations is to properly associate the biological responses with chemical and morphological properties of graphene. Several studies also report the environmental and genotoxicity response of pristine and functionalized graphene. This review summarizes these in vitro and in vivo studies and critically examines the methodologies used to perform these evaluations. Our overarching goal is to provide a comprehensive overview of the complex interplay of biological responses of graphene as a function of their physio-chemical properties.