Bronchiectasis pathophysiology is heterogeneous, complex and poorly understood. Cole’s vicious cycle hypothesis has been central to our understanding of the development and progression of bronchiectasis since the 1980s. This concept allowed us to focus on four different components: inflammation, airway structural damage, impaired mucociliary clearance and infection. Infection is the dominant stimulus for neutrophil recruitment to the airway and is considered to be a major driver of disease progression in bronchiectasis. Although bacterial pathogens are the most clinically important, mycobacteria, viruses and fungi are also identified in stable bronchiectasis, and contribute to disease phenotype and progression. Exacerbations in bronchiectasis are likely to be heterogeneous events with multiple potential causative factors. Dysfunction of cilia and an increase of mucus leaves the respiratory epithelium vulnerable to infection. Ciliary dysfunction can be primary or acquired through inflammation and infection. New technologies including whole-genome sequencing, metagenomics and big data are increasing our ability to cut through the heterogeneity of disease. Significant progress has been made in our understanding of the pathophysiology of bronchiectasis; however, there are many unanswered questions necessitating a renewed effort by the scientific community.