Herein, we present and discuss toxicological issues associated with the modification of living cell surfaces with nanomaterials. First, methods used for evaluation of the cell toxicity including approaches based on probing integrity of cell membrane, cell growth and activation of cell functionality are presented and discussed. Next, cytotoxic effects of polymers with respect to their charge, size, and architecture, and various nanomaterials, including metal and metal-oxide nanoparticles and carbon-based materials, on various types of cells are summarized with respect to the architectural differences of modified cells. Finally, cell surface-modification approaches including multilayer assembly of polymers, formation of nanothin organic and solid inorganic shells are analyzed with regard to their cytocompatibility.