Physical weakness and fatigue are common manifestations, both in health and disease. They represent adaptations of the neuromuscular system that have been the focus of many studies over the past decades. Still, the mechanisms underlying these phenomena remain poorly understood and an extensive body of the literature continues debating a central vs. peripheral origin of neuromuscular fatigue. However, in the quest of a unifying "fatigue" theory, some important factors might have been forgotten and possibly explain the lack of understanding of the specific mechanisms responsible for task failure and neuromuscular fatigue, respectively. The present work started out by addressing essential methodological concerns before moving on studying neuromuscular fatigue and weakness, and their underlying mechanisms. The main findings were that: (i) neuromuscular fatigue and weakness are two distinct phenomena underpinned by different mechanisms, (ii) depending on exercise intensity, task failure might occur as a consequence of either a critical neuromuscular fatigue or a critical neuromuscular reserve being reached, and (iii) the main origin of neuromuscular fatigue (central vs. peripheral) might depend on the muscle group(s) considered.