Applications of nanotechnology and material sciences emerge in the development of various novel drug delivery systems that have been proven as promising clinically. Among these, liposomes, noisome, polymeric carriers and lipid-based delivery system were extensively explored and enter into clinical trials and clinical applications. However, each system has its own pros and cons in term of different physicochemical, pharmacokinetics and therapeutics aspects. Lipid-polymer hybrid carriers merge the potential benefit of these structural components and can be prepared by different approaches to improve the therapeutic outcomes. In this chapter, we provide the useful insight about the lipid-polymer hybrid nanoparticles (LPHNPs) that can be prepared by using the different structural components including the synthetic and natural polymers and lipids. Among these, we also explain the various methods to prepare the LPHNPs with various desired characteristics. Finally, the various therapeutic and clinical applications have been presented briefly