<p>Conventional liposomes face major clinical limitations, including instability, rapid systemic clearance, and limited tumor targeting. This has driven extensive research into liposome functionalization for cancer therapy. In this review, peer-reviewed studies published between 1984 and 2025 were systematically analyzed to summarize recent advances in lipid-based functionalization strategies for improving liposomal drug delivery. Emphasis is placed on the optimization of lipid composition, particularly the roles of cholesterol and different phospholipids in regulating membrane fluidity, encapsulation efficiency (EE), and structural stability for the delivery of anticancer agents (ACAs). The application of polyethylene glycol (PEG) as a stealth polymer to extend circulation time is critically examined alongside its associated challenges. This includes the accelerated blood clearance (ABC) phenomenon, PEG-related immunogenicity, and optimal PEG densities, all of which can limit clinical performance like cellular uptake and drug delivery. Furthermore, this review discusses surface functionalization with targeting ligands such as antibodies, peptides, aptamers, and small molecules to promote receptor-mediated uptake and enhance tumor accumulation. This review highlights critical gaps in the optimization of PEG and ligand densities, in vivo understanding of PEGylated liposome behavior, and the rational design of surface linkers for balancing stealth and targeting efficiency. By integrating these findings, this work provides design-oriented insights for optimizing functionalized liposomes. Tunable lipid composition, stealth coating, and ligand selection can be strategically combined to improve formulation performance. These parameters can be tailored according to tumor receptor expression profiles and specific therapeutic requirements, moving toward more rationally designed liposomal systems with improved clinical translatability in cancer nanomedicine.</p>