Despite advances in pharmacological treatments, chronic fatigue remains an unresolved issue for most people with inflammatory arthritis, severely disrupting their personal and working lives. Their fatigue does not strongly link with peripheral disease activity, but instead, associates with central nervous system-derived symptoms like chronic pain, sleep disturbance and depression. Thus, a neurobiological basis should be considered when pursuing novel fatigue-specific therapeutics. In this review, we will first focus on clinical imaging biomarkers that map candidate brain regions, critical in fatigue pathophysiology. Then we will evaluate neuromodulation techniques that could affect these culprit brain regions, serving as potential treatment strategies for fatigue in inflammatory arthritis. We will conclude with what work still needs to be done for neuroimaging and neuromodulation to become a part of a future clinical pathway to treat and manage fatigue.