Nanoparticles have attracted much attention as a key material for new biomedical and pharmaceutical applications. For success in these applications, the nanoparticles are required to translocate across the cell membrane and to reach to inside of the cell. Among several translocation pathways of nanoparticles, the direct permeation pathway has a great advantage due to its high delivery efficacy. However, despite many research efforts, key properties and factors for driving the direct permeation of nanoparticle and its underlying mechanisms are far from being understood. In this article, experimental and computational studies regarding the direct permeation of nanoparticles across a cell membrane will be reviewed. Firstly, experimental studies on the nanoparticle-cell interactions, where spontaneous direct permeation of nanoparticles was observed, are reviewed. From the experimental studies, potential key physico-chemical properties of nanoparticles for their direct permeation are discussed. Secondly, physical methods such as electroporation and sonoporation for delivering nanoparticles into cells are reviewed. Current status of technologies for facilitating the direct permeation of nanoparticle is presented. Finally, we review molecular dynamics simulation studies and present the latest findings on the underlying molecular mechanisms of the direct permeation of nanoparticle.