Natively unfolded proteins, or intrinsically disordered proteins, challenge the traditional structure–function paradigm in protein biology, which posits that a protein's function is determined by its rigid three-dimensional structure. This review discusses the structural diversity of natively unfolded proteins, which can be divided into two groups: intrinsic coils and premolten globules. Intrinsic coils have hydrodynamic dimensions typical of random coils in poor solvent and lack ordered secondary structure, while premolten globules are more compact and exhibit some residual secondary structure but are still less dense than native or molten globule proteins. These proteins undergo a disorder–order transition during or prior to their biological function, a concept explored through the Protein Quartet model, which includes four conformations: ordered forms, molten globules, premolten globules, and random coils, with transitions between any two states. The review highlights that a significant portion of proteins may lack ordered structure under physiological conditions, challenging the structure–function paradigm. Techniques such as proteomics, NMR spectroscopy, and hydrodynamic measurements have revealed that natively unfolded proteins exhibit a range of conformations, including molten globules and premolten globules, which are distinct thermodynamic states. These proteins are characterized by low hydrophobicity and high net charge, and their amino acid sequences often show low complexity. The review also discusses the functional importance of intrinsic disorder, noting that it allows for flexibility and adaptability, enabling proteins to perform diverse biological functions. Intrinsically disordered proteins can undergo disorder-to-order transitions during their function, which may be advantageous for evolution. The Protein Quartet model extends the Protein Trinity paradigm, incorporating four conformations and transitions between them, providing a more comprehensive framework for understanding protein function. The review concludes that natively unfolded proteins are common and play important roles in various biological processes, challenging the traditional view of protein structure and function.Natively unfolded proteins, or intrinsically disordered proteins, challenge the traditional structure–function paradigm in protein biology, which posits that a protein's function is determined by its rigid three-dimensional structure. This review discusses the structural diversity of natively unfolded proteins, which can be divided into two groups: intrinsic coils and premolten globules. Intrinsic coils have hydrodynamic dimensions typical of random coils in poor solvent and lack ordered secondary structure, while premolten globules are more compact and exhibit some residual secondary structure but are still less dense than native or molten globule proteins. These proteins undergo a disorder–order transition during or prior to their biological function, a concept explored through the Protein Quartet model, which includes four conformations: ordered forms, molten globules, premolten globules, and random coils, with transitions between any two states. The review highlights that a significant portion of proteins may lack ordered structure under physiological conditions, challenging the structure–function paradigm. Techniques such as proteomics, NMR spectroscopy, and hydrodynamic measurements have revealed that natively unfolded proteins exhibit a range of conformations, including molten globules and premolten globules, which are distinct thermodynamic states. These proteins are characterized by low hydrophobicity and high net charge, and their amino acid sequences often show low complexity. The review also discusses the functional importance of intrinsic disorder, noting that it allows for flexibility and adaptability, enabling proteins to perform diverse biological functions. Intrinsically disordered proteins can undergo disorder-to-order transitions during their function, which may be advantageous for evolution. The Protein Quartet model extends the Protein Trinity paradigm, incorporating four conformations and transitions between them, providing a more comprehensive framework for understanding protein function. The review concludes that natively unfolded proteins are common and play important roles in various biological processes, challenging the traditional view of protein structure and function.