The carbon-based nanomaterials (CNMs) such as graphene oxide (GO) and carbon nanofibers (CNFs) are generally considered safe materials. However, recent studies indicate that they can pose risk for human health and living systems depending on their exposure route and dose. The diversity in their lateral and longitudinal sizes and shape increase their potential risk. Although several studies demonstrate that surface chemistry can alter the toxic behavior of nanomaterials, it is not clear for every type of NMs. In order to implement the Safe-by Design approach, in this study, the influence of surface chemistry of carbon-based nanomaterials on their cytotoxicity and genotoxicity is investigated. Two CNMs, GO and CNFs, are modified with glycine, a simplest amino acid, and glucose, a monosaccharide, and evaluated for their cytotoxicity and genotoxicity using cell lines, HSF (human skin fibroblast), RAW264.7 (macrophage) and BEAS-2B (human bronchial lung epithelial). It was found that surface chemistry was a significant factor determining the cellular response.