Breathlessness is a common symptom in respiratory, cardiovascular and malignant disease. It reduces exercise tolerance and mobility, and is an important determinant of quality of life. The multifactorial nature of the symptom often presents difficulties in understanding why individual patients are breathless, and how breathlessness should best be palliated, especially in advanced disease. However, insights into the neurophysiological factors underlying the symptom can be gained by considering the balance between the load on, and capacity of, the respiratory muscles and increased neural respiratory drive, reflecting increased respiratory effort. Mismatch between efferent neural respiratory drive and afferent feedback, reflecting the degree of neuromechanical dissociation, is also important. This paper describes mechanisms by which ventilatory load, capacity and drive may be affected by disease, and how these can be measured physiologically. The schema presented also provides a framework for understanding the mechanisms by which interventions that relieve breathlessness may have their effect.