Fatigue has been defined differently in the past depending on the field of research (e.g., psychology, exercise physiology, neuroscience, and medical fields), which has led to an inconsistent use of the term, thereby limiting scientific progress and communication. Hence, it is first of all important to differentiate between trait fatigue and state fatigue. Trait fatigue describes the fatigue experienced by an individual over a longer period of time (e.g., weeks and months), which is relatively stable and a symptom of various diseases (e.g., multiple sclerosis, chronic obstructive pulmonary disease, and rheumatoid arthritis). Activity-induced state fatigue, in turn, is characterized by an acute and temporary change in motor or cognitive performance (i.e., motor or cognitive performance fatigue, respectively) as well as the subjective experience of weariness or exhaustion (i.e., perceived motor or cognitive fatigue, respectively) that occur in the context of a specific motor or cognitive task. In the context of this cumulative habilitation, seven studies investigating different aspects of activity-induced state fatigue were carried out and are presented in this scientific work. Three studies investigated basic mechanisms of state fatigue in response to motor and cognitive tasks. While the motor tasks included repetitive jumping until exhaustion and 2000-m rowing, the cognitive task consisted of performing an inhibition task for 90 min. The other four experiments tried to manipulate the determinants of motor task-induced state fatigue to gain insights into the contributing mechanisms. The applied interventions included endurance training, blood flow restriction exercise, dietary nitrate supplementation, and ischemic preconditioning. The results of the experimental studies have assisted in updating a recently published definition and framework of fatigue, which was addressed, among other things, in three narrative reviews included in this work. Findings of the experimental studies and review articles belonging to this habilitation indicate that performance fatigue and perceived fatigue in response to motor and cognitive tasks as well as their determinants are task-dependent and interdependent. Therefore, the different aspects of these state fatigue dimensions should be considered in combination to unravel the psychophysiology underlying the performance during sustained motor and cognitive tasks. Consequently, there is no single factor primarily determining performance fatigue and perceived fatigue, but the relative weight of each determinant and their interaction depends on several modulating factors (e.g., age, sex, diseases, and characteristics of the task). Hence, a combined measurement of performance fatigue and perceived fatigue together with its (neuro)physiological correlates is necessary to decipher the psychophysiology of motor and cognitive task-induced state fatigue. This knowledge will assist to better understand the interactions between the different dimensions of state fatigue and their effect on human performance in health and disease. This is crucial to design and plan effective interventions for increasing exercise tolerance, which is of particular importance for vulnerable, deconditioned, and clinical populations.