INTRODUCTION: The use of liposomes increases the therapeutic index of many drugs, and also offers drug targeting and controlled release. The commercial impact of liposomes is strengthened by the invention of several active drug encapsulation methods, allowing the encapsulation of several weak base or weak acid drugs with very high drug-to-lipid ratios. AREAS COVERED: In recent years, there have been reports on several new approaches to retain more hydrophobic drugs inside liposomes, in the circulation. Most of these methods apply drug precipitation inside preformed liposomes, as low soluble complexes with ions or chemicals. In some cases, drug derivatization was applied to enable active encapsulation of hydrophobic drugs, previously not reported to encapsulate, by active or remote loading. This review presents and compares most of the existing methods of active drug encapsulation and outlines recent strategies to achieve stable drug encapsulation in vivo. EXPERT OPINION: At present, there is no single universal encapsulation method that offers stable encapsulation of most drugs; each drug requires a different approach to manage all of its properties. Now is the time to combine all these strategies to achieve the goal of a complex, but successful, anticancer therapy.