With the advancements in nanotechnology, studies on the synthesis, modification, application, and toxicology evaluation of nanomaterials are gaining increased attention. In particular, the applications of nanomaterials in biological systems are attracting considerable interest because of their unique, tunable, and versatile physicochemical properties. Artificially engineered nanomaterials can be well controlled for appropriate usage, and the tuned physicochemical properties directly influence the interactions between nanomaterials and cells. This review summarizes recently synthesized major nanomaterials that have potential biomedical applications. Focus is given on the interactions, including cellular uptake, intracellular trafficking, and toxic response, while changing the physicochemical properties of versatile materials. The importance of physicochemical properties such as the size, shape, and surface modifications of the nanomaterials in their biological effects is also highlighted in detail. The challenges of recent studies and future prospects are presented as well. This review benefits relatively new researchers in this area and gives them a systematic overview of nano-bio interaction, hopefully for further experimental design.