The purpose of this review is to provide an overview on how interactions between control of breathing, respiratory load, and muscle function may lead to respiratory failure. The mechanisms involved vary according to the underlying pathology, but respiratory failure is most often the result of an imbalance between the muscular pump and the mechanical load placed upon it. Changes in respiratory drive and response to CO2 seem to be important contributors to the pathophysiology of respiratory failure. Inspiratory muscle dysfunction is also frequent but is not a mandatory prerequisite to respiratory failure since increased load may also be sufficient to precipitate it. It is crucial to recognize these interactions to be able to timeously establish patients on mechanical ventilation and adapt the ventilator settings to their respiratory system physiology.