The in vivo fate of lipid-based nanoparticles (LBNs) is essentially determined by the properties of their lipid compositions. LBNs are rapidly degraded via lipolysis wherever lipases are abundant, especially in the gastrointestinal tract. LBNs that survive lipolysis can be translocated through the circulation to reach terminal organs or tissues. Lipid composition, particle size, and surface decoration, as well as the formation of protein corona, are the main factors influencing the in vivo fate of LBNs. As we discuss here, elucidation of the in vivo fate of LBNs helps weigh the balance between lipolysis and biorecognition, and is emerging as a new field of research.