Synthetic nanocarriers continue to play an important role in nanomedicine as the next generation of therapeutics demands effective intracellular delivery. Better understanding of the extra- and intra-cellular fate of the nanocarriers in relation with biological environments in vitro and in vivo is essential for the progress of nanocarrier-based therapeutics. As nanocarriers come into contact with biological fluid, interactions with various biomolecules alter their initial physicochemical status. Such dynamic modifications influence their interactions with cells and the subsequent endocytic process. Upon cellular uptake, intracellular machineries control their trafficking, release and degradation of cargoes, and exocytosis. In this Review, we highlight the navigation of nanocarriers through various extra- and intra-cellular barriers, with an emphasis on how dynamic interactions with biological components alter their fate and performance. (C) 2017 Elsevier Ltd. All rights reserved.