To control interactions between cells and nanomaterials has been a great challenge because numerous nanomaterials have been intensively explored in the fields of biology and medicine. However, current surface modification of nanomaterials is mainly carried out in an empirical way. Herein, a general strategy to tune the surface chemistry of nanomaterials is proposed based on cell affinity, that is, cytophilic or cytophobic. The cell affinity of nanomaterials directly affects cellular response to materials at the very early stage of cell–material interactions before other events, such as endocytosis, cell spreading, and cell differentiation, occur. In this Concept, it is suggested that there is a developing library of cytophilic and cytophobic moieties, and how the cell affinity of nanomaterials functions at biointerfaces is discussed by exemplifying several applications, namely therapy, tissue engineering, and biosensors. It is believed that control of the cytophilic/cytophobic property will be helpful in guiding the design of functional nanomaterials for their biomedical applications.