This review provides an in-depth analysis of the endocytosis mechanisms of nanomedicines, which are novel nanomaterials designed for improved diagnosis and therapy of diseases. The review classifies various endocytic pathways, including phagocytosis and pinocytosis, and discusses the experimental tools used to study these processes. It highlights specific examples from recent literature and the authors' own work to explore how particle size, shape, material composition, surface chemistry, and charge influence the selection of endocytic pathways. The effect of cell type on nanomedicine processing and the impact of nanomaterial-cell interactions on endocytosis, cellular responses, and nanomedicine fate are also examined. The review covers phagocytosis, clathrin-dependent endocytosis, caveolae-mediated endocytosis, clathrin- and caveolae-independent endocytosis, macropinocytosis, and the use of nanomaterials employing multiple entry pathways. It emphasizes the importance of understanding these mechanisms for optimizing the delivery and therapeutic effects of nanomedicines.This review provides an in-depth analysis of the endocytosis mechanisms of nanomedicines, which are novel nanomaterials designed for improved diagnosis and therapy of diseases. The review classifies various endocytic pathways, including phagocytosis and pinocytosis, and discusses the experimental tools used to study these processes. It highlights specific examples from recent literature and the authors' own work to explore how particle size, shape, material composition, surface chemistry, and charge influence the selection of endocytic pathways. The effect of cell type on nanomedicine processing and the impact of nanomaterial-cell interactions on endocytosis, cellular responses, and nanomedicine fate are also examined. The review covers phagocytosis, clathrin-dependent endocytosis, caveolae-mediated endocytosis, clathrin- and caveolae-independent endocytosis, macropinocytosis, and the use of nanomaterials employing multiple entry pathways. It emphasizes the importance of understanding these mechanisms for optimizing the delivery and therapeutic effects of nanomedicines.