This review provides a comprehensive overview of protein-ligand interactions, focusing on the mechanisms, models, and methods used to study these interactions. The first part of the review introduces the physicochemical mechanisms underlying protein-ligand binding, including binding kinetics, thermodynamic concepts, and driving forces. It discusses the importance of binding kinetics in determining the binding rate and the role of thermodynamic parameters such as enthalpy and entropy in governing the stability of the complex. The second part describes three prominent models of protein-ligand binding: the "lock-and-key," "induced fit," and "conformational selection." Each model is explained in detail, highlighting the underlying thermodynamic mechanisms and their implications for understanding protein-ligand interactions. The third part focuses on experimental and theoretical methods used to investigate protein-ligand binding affinity. Experimental methods such as isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), and fluorescence polarization (FP) are discussed, along with their advantages, disadvantages, and challenges. The computational methods, including protein-ligand docking and free energy calculations, are also covered, emphasizing their role in predicting binding modes and affinities. The review concludes by discussing the interplay between the lock-and-key, induced fit, and conformational selection models, highlighting how they can coexist or operate sequentially in different binding events. It emphasizes the importance of understanding these mechanisms for advancing the fields of molecular recognition, drug design, and biological research.This review provides a comprehensive overview of protein-ligand interactions, focusing on the mechanisms, models, and methods used to study these interactions. The first part of the review introduces the physicochemical mechanisms underlying protein-ligand binding, including binding kinetics, thermodynamic concepts, and driving forces. It discusses the importance of binding kinetics in determining the binding rate and the role of thermodynamic parameters such as enthalpy and entropy in governing the stability of the complex. The second part describes three prominent models of protein-ligand binding: the "lock-and-key," "induced fit," and "conformational selection." Each model is explained in detail, highlighting the underlying thermodynamic mechanisms and their implications for understanding protein-ligand interactions. The third part focuses on experimental and theoretical methods used to investigate protein-ligand binding affinity. Experimental methods such as isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), and fluorescence polarization (FP) are discussed, along with their advantages, disadvantages, and challenges. The computational methods, including protein-ligand docking and free energy calculations, are also covered, emphasizing their role in predicting binding modes and affinities. The review concludes by discussing the interplay between the lock-and-key, induced fit, and conformational selection models, highlighting how they can coexist or operate sequentially in different binding events. It emphasizes the importance of understanding these mechanisms for advancing the fields of molecular recognition, drug design, and biological research.