This chapter overviews the attempts in understanding the biocompatibility of nanomaterials and provides an account of how these views changed in light of recent findings, with emphasis on the methodology used in nanotoxicology studies. The excretion and clearance of engineered nanomaterials (ENMs) is discussed in the chapter, but it should be noted that cells themselves respond to ENMs by activating their exocytosis mechanisms, thus extruding or degrading ENMs at the subcellular level. Although the in vitro tests previously outlined in the chapter provide means of predicting the behavior of nanomaterials, it is nonetheless possible that unforeseen in vivo effects may occur. As with any material intended for human use, their safety must first and foremost be investigated to sufficient detail, through both in vitro experiments and animal studies, before they can be administered to human patients.