Polymeric micelles (PM) have been extensively used for tumor-targeted delivery of hydrophobic anti-cancer drugs. The lipophilic core of PM is naturally suitable for loading hydrophobic drugs and the hydrophilic shell endows them with colloidal stability and stealth properties. Decades of research on PM have resulted in tremendous numbers of PM-forming amphiphilic polymers, and approximately a dozen micellar nanomedicines have entered the clinic. The first generation of PM can be considered solubilizers of hydrophobic drugs, with short circulation times resulting from poor micelle stability and unstable drug entrapment. To more optimally exploit the potential of PM for targeted drug delivery, several physical (e.g., π–π stacking, stereocomplexation, hydrogen bonding, host–guest complexation, and coordination interaction) and chemical (e.g., free radical polymerization, click chemistry, disulfide and hydrazone bonding) strategies have been developed to improve micelle stability and drug retention. In this review, the most promising physico-chemical approaches to enhance micelle stability and drug retention are described, and how these strategies have resulted in systems with promising therapeutic efficacy in animal models, paving the way for clinical translation, is summarized.