This review provides a comprehensive overview of the cellular uptake of nanoparticles (NPs) and the underlying parameters controlling their interactions with cells. NPs, which are increasingly used in various applications, can modulate cell fate, induce or prevent mutations, and influence cell communication and structure. The review highlights the importance of the protein corona, which forms on NPs in biological fluids, and how it affects their interaction with cells. It also discusses the role of the microenvironment, including factors such as pH and extracellular matrix, in altering NP properties and their interactions with cell membranes. The text delves into the mechanisms of NP entry into cells, including phagocytosis, clathrin-mediated endocytosis, caveolae-mediated endocytosis, clathrin/caveolae-independent endocytosis, and macropinocytosis. Each mechanism is described in detail, along with the factors that influence their efficiency, such as NP size, shape, surface charge, and hydrophobicity. The review also explores the impact of NP physicochemical properties on their cellular uptake, emphasizing the importance of size, shape, and surface charge in determining the NP's fate within the cell. Additionally, it discusses the role of surface charge and hydrophobicity in NP-membrane interactions and their effects on membrane disruption and NP internalization. Overall, the review aims to provide a detailed understanding of the complex processes involved in NP cellular uptake and the factors that govern these processes.This review provides a comprehensive overview of the cellular uptake of nanoparticles (NPs) and the underlying parameters controlling their interactions with cells. NPs, which are increasingly used in various applications, can modulate cell fate, induce or prevent mutations, and influence cell communication and structure. The review highlights the importance of the protein corona, which forms on NPs in biological fluids, and how it affects their interaction with cells. It also discusses the role of the microenvironment, including factors such as pH and extracellular matrix, in altering NP properties and their interactions with cell membranes. The text delves into the mechanisms of NP entry into cells, including phagocytosis, clathrin-mediated endocytosis, caveolae-mediated endocytosis, clathrin/caveolae-independent endocytosis, and macropinocytosis. Each mechanism is described in detail, along with the factors that influence their efficiency, such as NP size, shape, surface charge, and hydrophobicity. The review also explores the impact of NP physicochemical properties on their cellular uptake, emphasizing the importance of size, shape, and surface charge in determining the NP's fate within the cell. Additionally, it discusses the role of surface charge and hydrophobicity in NP-membrane interactions and their effects on membrane disruption and NP internalization. Overall, the review aims to provide a detailed understanding of the complex processes involved in NP cellular uptake and the factors that govern these processes.