Because the diaphragm is essential for survival, we wondered if it might be less vulnerable to the long-lasting effects of fatigue than limb muscles. Using a recently introduced magnetic probe to activate the phrenic nerves, we followed the evolution of twitch transdiaphragmatic pressure after inducing fatigue in healthy volunteers. Twenty-four hours after its induction, diaphragmatic fatigue had not fully recovered. Findings from this study later served as the foundation for incorporating a once-daily, T-tube-trial arm into a randomized controlled trial of techniques for ventilator weaning in intensive care unit patients and also influenced the design of a controlled trial of the weaning of tracheostomy patients who required prolonged ventilation. The research methodology was later employed to determine whether low-frequency fatigue is responsible for weaning failure. Employing a further modification of the technique--twitch airway pressure--it became evident that respiratory muscle weakness is a greater problem than fatigue in ventilated patients. Twitch airway pressure is now being used to document the prevalence and consequences of ventilator-induced respiratory muscle weakness. Our study--which began with a circumscribed, simple question--has yielded dividends in unforeseen directions, illustrating the fruitfulness of research into basic physiological mechanisms.