Many consider carbon nanomaterials the poster children of nanotechnology, attracting immense scientific interest from many disciplines and offering tremendous potential in a diverse range of applications due to their extraordinary properties. Graphene is the youngest in the family of carbon nanomaterials. Its isolation, description, and mass fabrication has followed that of fullerenes and carbon nanotubes. Graphene’s development and its adoption by many industries will increase unintended or intentional human exposure, creating the need to determine its safety profile. In this Account, we compare the lessons learned from the development of carbon nanotubes with what is known about graphene, based on our own investigations and those of others. Despite both being carbon-based, nanotubes and graphene are two very distinct nanomaterials. We consider the key physicochemical characteristics (structure, surface, colloidal properties) for graphene and carbon nanotubes at three different physiological levels: cellular, tissue, and whole body. We summarize the evidence for health effects of both materials at all three levels. Overall, graphene and its derivatives are characterized by a lower aspect ratio, larger surface area, and better dispersibility in most solvents compared to carbon nanotubes. Dimensions, surface chemistry, and impurities are equally important for graphene and carbon nanotubes in determining both mechanistic (aggregation, cellular processes, biodistribution, and degradation kinetics) and toxicological outcomes. Colloidal dispersions of individual graphene sheets (or graphene oxide and other derivatives) can easily be engineered without metallic impurities, with high stability and less aggregation. Very importantly, graphene nanostructures are not fiber-shaped. These features theoretically offer significant advantages in terms of safety over inhomogeneous dispersions of fiber-shaped carbon nanotubes. However, studies that directly compare graphene with carbon nanotubes are rare, making comparative considerations of their overall safety and risk assessment challenging. In this Account, we attempt to offer a set of rules for the development of graphene and its derivatives to enhance their overall safety and minimize the risks for adverse reactions in humans from exposure. These rules are: (1) to use small, individual graphene sheets that macrophages in the body can efficiently internalize and remove from the site of deposition; (2) to use hydrophilic, stable, colloidal dispersions of graphene sheets to minimize aggregation in vivo; and (3) to use excretable graphene material or chemically-modified graphene that can be degraded effectively. Such rules can only act as guidelines at this early stage in the development of graphene-based technologies, yet they offer a set of design principles for the fabrication and safe use of graphene material that will come in contact with the human body. In a broader context, the safety risks associated with graphene materials will be entirely dependent on the specific types of graphene materials and how they are investigated or applied. Therefore, generalizations about the toxicity of “graphene” as a whole will be inaccurate, possibly misleading, and should be avoided.