Here, we report methods of preparation for liposome formulations containing lipophilic drugs. In contrast to the encapsulation of water-soluble compounds into the entrapped aqueous volume of a liposome, drugs with lipophilic properties are incorporated into the phospholipid bilayer membrane. Water-soluble molecules, for example, cytotoxic or antiviral nucleosides can be transformed into lipophilic compounds by attachment of long alkyl chains, allowing their stable incorporation into liposome membranes and taking advantage of the high loading capacity lipid bilayers provide for lipophilic molecules. We created a new class of cytotoxic drugs by chemical transformation of the hydrophilic drugs cytosine-arabinoside (ara-C), 5-fluoro-deoxyuridine (5-FdU) and ethinylcytidine (ETC) into lipophilic compounds and their formulation in liposomes. The concept of chemical modification of water-soluble molecules by attachment of long alkyl chains and their stable incorporation into liposome bilayer membranes represent a very promising method for the development of new drugs not only for the treatment of tumors or infections, but also for many other diseases.