The in vivo fate of lipid-based nanoparticles (LBNs) is essentially determined by the properties of their lipid compositions. The article focuses on how important is to find a balance between the degradation and translocation of LBNs. LBNs degrade in the body via lipolysis, whose rate depends on the lipid composition, particle size, surface decoration, presence of lipases. It is also certain that LBNs might not be broken down instantly and can survive for some time, which provides opportunities for them to be used as nanocarriers for drug delivery.