Nanomedicines are nanoscale materials designed to deliver drugs, biopharmaceuticals, and imaging agents to target cells for improved diagnosis and therapy. Effective delivery requires site-specific cellular entry, often through endocytosis, which involves multiple pathways such as phagocytosis, pinocytosis (clathrin-dependent and clathrin-independent), and macropinocytosis. This review discusses the mechanisms of endocytosis, current experimental tools for studying it, and examples from recent literature and the authors' work. It highlights how factors like particle size, shape, material composition, and surface chemistry influence the choice of endocytic pathway. The review also explores how cell type and nanomaterial-cell interactions affect nanomaterial processing, trafficking, and cellular responses. Phagocytosis is primarily used by professional phagocytes like macrophages, but some non-professional phagocytes may also exhibit phagocytic activity. Clathrin-dependent endocytosis (CME) is a classical pathway for nutrient uptake and is active in all mammalian cells. CME involves the formation of coated pits and vesicles, which are then sorted to endosomes, lysosomes, or the trans-Golgi network. Caveolae-mediated endocytosis is another pathway, involving lipid rafts and caveolin-1, and is important for transendothelial transport. Clathrin- and caveolae-independent pathways include Arf6-dependent, flotillin-dependent, Cdc42-dependent, and RhoA-dependent endocytosis. Macropinocytosis is a large-scale process involving membrane ruffles and is independent of clathrin, caveolae, and dynamin. Various nanomaterials, such as poly(ethylene glycol)-polylactide nanoparticles, PLGA nanoparticles, silica-based nanomaterials, chitosan nanoparticles, and Abraxane, have been shown to utilize different endocytic pathways. For example, poly(ethylene glycol)-polylactide nanoparticles enter cells via CME in some cell types and via caveolae-mediated endocytosis in others. PLGA nanoparticles can enter cells through CME or caveolae-independent pathways depending on the cell type. Silica-based nanomaterials and chitosan nanoparticles also use CME for entry. Abraxane utilizes caveolae-mediated transcytosis for efficient drug delivery. The review emphasizes the importance of understanding endocytic pathways for the development of effective nanomedicines, as the choice of pathway can significantly impact the fate of nanomaterials and their therapeutic efficacy. The analysis also highlights the need for further research to fully understand the complex interactions between nanomaterials and cells.Nanomedicines are nanoscale materials designed to deliver drugs, biopharmaceuticals, and imaging agents to target cells for improved diagnosis and therapy. Effective delivery requires site-specific cellular entry, often through endocytosis, which involves multiple pathways such as phagocytosis, pinocytosis (clathrin-dependent and clathrin-independent), and macropinocytosis. This review discusses the mechanisms of endocytosis, current experimental tools for studying it, and examples from recent literature and the authors' work. It highlights how factors like particle size, shape, material composition, and surface chemistry influence the choice of endocytic pathway. The review also explores how cell type and nanomaterial-cell interactions affect nanomaterial processing, trafficking, and cellular responses. Phagocytosis is primarily used by professional phagocytes like macrophages, but some non-professional phagocytes may also exhibit phagocytic activity. Clathrin-dependent endocytosis (CME) is a classical pathway for nutrient uptake and is active in all mammalian cells. CME involves the formation of coated pits and vesicles, which are then sorted to endosomes, lysosomes, or the trans-Golgi network. Caveolae-mediated endocytosis is another pathway, involving lipid rafts and caveolin-1, and is important for transendothelial transport. Clathrin- and caveolae-independent pathways include Arf6-dependent, flotillin-dependent, Cdc42-dependent, and RhoA-dependent endocytosis. Macropinocytosis is a large-scale process involving membrane ruffles and is independent of clathrin, caveolae, and dynamin. Various nanomaterials, such as poly(ethylene glycol)-polylactide nanoparticles, PLGA nanoparticles, silica-based nanomaterials, chitosan nanoparticles, and Abraxane, have been shown to utilize different endocytic pathways. For example, poly(ethylene glycol)-polylactide nanoparticles enter cells via CME in some cell types and via caveolae-mediated endocytosis in others. PLGA nanoparticles can enter cells through CME or caveolae-independent pathways depending on the cell type. Silica-based nanomaterials and chitosan nanoparticles also use CME for entry. Abraxane utilizes caveolae-mediated transcytosis for efficient drug delivery. The review emphasizes the importance of understanding endocytic pathways for the development of effective nanomedicines, as the choice of pathway can significantly impact the fate of nanomaterials and their therapeutic efficacy. The analysis also highlights the need for further research to fully understand the complex interactions between nanomaterials and cells.