Molecular crowding, the phenomenon where biological macromolecules are surrounded by other molecules in a crowded environment, has become a central concept in biophysics. This review explores the history and development of the crowding concept, tracing its origins in polymer physics and colloidal science to its current biological applications. Initially, the concept was rooted in entropy-driven effects, where the presence of crowders reduced the available volume for other molecules, influencing their conformation and interactions. Over time, the role of enthalpy became recognized, highlighting the complex interplay between entropy and enthalpy in determining protein stability and dynamics. The review discusses the evolution of models for molecular crowding, starting with early theoretical frameworks like the AO model, which described depletion interactions in colloid-polymer mixtures. These models were later validated experimentally, leading to a deeper understanding of phase behavior and the effects of crowding on protein stability and dynamics. The concept of crowding has also been extended to include the role of different crowders, such as proteins and synthetic polymers, and their impact on cellular processes like phase separation and biomolecular condensation. The review highlights the importance of considering both entropic and enthalpic effects in understanding how crowding influences biological systems. It also addresses the challenges in experimental validation, including the difficulty of isolating the effects of crowding from other factors like cosolutes and the complexity of cellular environments. The study of molecular crowding has led to the development of various models and techniques, including the use of synthetic crowders and in vitro mimics of cellular environments, to better understand the role of crowding in biological processes. Overall, the concept of molecular crowding has evolved from a simple entropy-driven effect to a complex interplay of physical and chemical interactions that shape the behavior of biomolecules in cellular environments. The review underscores the importance of this concept in understanding the function and dysfunction of biological systems, and the need for further research to fully elucidate the role of crowding in cellular processes.Molecular crowding, the phenomenon where biological macromolecules are surrounded by other molecules in a crowded environment, has become a central concept in biophysics. This review explores the history and development of the crowding concept, tracing its origins in polymer physics and colloidal science to its current biological applications. Initially, the concept was rooted in entropy-driven effects, where the presence of crowders reduced the available volume for other molecules, influencing their conformation and interactions. Over time, the role of enthalpy became recognized, highlighting the complex interplay between entropy and enthalpy in determining protein stability and dynamics. The review discusses the evolution of models for molecular crowding, starting with early theoretical frameworks like the AO model, which described depletion interactions in colloid-polymer mixtures. These models were later validated experimentally, leading to a deeper understanding of phase behavior and the effects of crowding on protein stability and dynamics. The concept of crowding has also been extended to include the role of different crowders, such as proteins and synthetic polymers, and their impact on cellular processes like phase separation and biomolecular condensation. The review highlights the importance of considering both entropic and enthalpic effects in understanding how crowding influences biological systems. It also addresses the challenges in experimental validation, including the difficulty of isolating the effects of crowding from other factors like cosolutes and the complexity of cellular environments. The study of molecular crowding has led to the development of various models and techniques, including the use of synthetic crowders and in vitro mimics of cellular environments, to better understand the role of crowding in biological processes. Overall, the concept of molecular crowding has evolved from a simple entropy-driven effect to a complex interplay of physical and chemical interactions that shape the behavior of biomolecules in cellular environments. The review underscores the importance of this concept in understanding the function and dysfunction of biological systems, and the need for further research to fully elucidate the role of crowding in cellular processes.