Lipids are biomolecules constituting the principal components of the living cells. Chemical association of drug molecules with lipids may alter their in vivo pharmacokinetics/pharmacodynamics and even, in certain cases, their toxicity profile. Successful design of a lipid–anticancer prodrug highly depends on the lipid’s carbon chain length, on the configuration of the double bonds, and on the location and nature of the covalent linkage with the drug. In general, well–designed lipid–anticancer prodrugs display better cellular penetration, controlled drug release property, better pharmacokinetics, improved tumor accumulation, and better cellular penetration leading to enhanced therapeutic activity and lower toxicity. Thus, the better therapeutic index results from a controlled exposure of the conjugated drug to the biological environment. Noteworthy, in the treatment of cancers, drug resistance is one of the most important clinical concerns. Thus, there is a real need to develop new chemical entities able to bypass the resistance factors, thus displaying an improved therapeutic response. In this context, lipid prodrugs of anticancer agents are important actors in overcoming the resistance to cancers, at least at the preclinical stage. This chapter aims to discuss in detail about the various lipids employed in anticancer drug delivery applications. The current stage of their development either preclinical or clinical is also presented.