Fatigue relief is possible.

Chronic fatigue is widely discussed across clinical and non-clinical contexts, yet its definition and measurement remain heterogeneous and debated. In this fragmented landscape, adopting an efficacy-informed perspective grounded in mitigating interventions offers a reliable pathway to delineate the core features and regulatory mechanisms of chronic fatigue. This Mini Review aims to identify and synthesize interventions shown to be effective in mitigating chronic fatigue. A preliminary screening was conducted using the terms "fatigue" AND ("relief" OR "mitigation" OR "treatment"), thereby inherently focusing on persistent and functionally impairing forms of fatigue. The analysis was then restricted to the most cited evidence to highlight the most consolidated findings. Four classes of behavioral interventions consistently emerged as effective across heterogeneous conditions (stroke, cancer, multiple sclerosis, traumatic brain injury, and non-clinical contexts): cognitive behavioral therapy, mindfulness-based approaches, yoga, and physical activity. Their convergence suggests that chronic fatigue reflects, rather than condition-specific processes, the alteration of shared regulatory mechanisms, likely involving neurophysiological dynamics and associated biological markers, which can be further elucidated by integrating evidence from effective interventions with their neurophysiological and biomarker correlates. The evidence from this Mini Review on the transversal effectiveness of the same interventions supports leveraging their efficacy and the associated neurophysiological and biochemical changes to identify sensitive markers that track treatment response and inform the underlying mechanisms of fatigue. Future research should therefore prioritize standardized measures, shared markers, and personalized interventions, potentially supported by biochemical and neuromodulatory approaches.