The respiratory mucus, a viscoelastic gel, plays a crucial role in the airway defense system through mucociliary clearance. In chronic respiratory diseases (CRDs) such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), the mucus production is increased, leading to changes in its structure and viscoelastic properties, which disrupt the normal defense mechanisms against pathogens. This results in airway damage and a vicious cycle of obstruction and infection, contributing to the severe clinical outcomes of these diseases. The review covers the essential features of normal and pathological mucus, including mucin content, structure, micro-/macro-rheology, pH, and osmotic pressure. It also discusses the potential of sputum biomarkers, such as mucins, inflammatory proteins, peptides, and metabolites, to indicate acute exacerbations and response to therapies. While some treatments show promise in altering mucus structure and properties, more research is needed to establish these measures as correlates of disease severity. The review highlights the complex interplay between mucus composition, viscoelasticity, and disease progression, emphasizing the need for a deeper understanding of these mechanisms to improve patient outcomes.The respiratory mucus, a viscoelastic gel, plays a crucial role in the airway defense system through mucociliary clearance. In chronic respiratory diseases (CRDs) such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), the mucus production is increased, leading to changes in its structure and viscoelastic properties, which disrupt the normal defense mechanisms against pathogens. This results in airway damage and a vicious cycle of obstruction and infection, contributing to the severe clinical outcomes of these diseases. The review covers the essential features of normal and pathological mucus, including mucin content, structure, micro-/macro-rheology, pH, and osmotic pressure. It also discusses the potential of sputum biomarkers, such as mucins, inflammatory proteins, peptides, and metabolites, to indicate acute exacerbations and response to therapies. While some treatments show promise in altering mucus structure and properties, more research is needed to establish these measures as correlates of disease severity. The review highlights the complex interplay between mucus composition, viscoelasticity, and disease progression, emphasizing the need for a deeper understanding of these mechanisms to improve patient outcomes.