The assessment and treatment of post-stroke shoulder pain (PSSP) is largely based on the assumption that pain is due to biomechanical alterations within the shoulder joint after stroke. However, current treatment often provides limited pain relief, leading to a considerable number of patients with persistent pain. This suggests that PSSP may not be merely due to simple nociception from the shoulder joint. A better understanding of the neurophysiological mechanisms underlying the development and perpetuation of PSSP is needed. Here, a theoretical framework for presumed PSSP mechanisms and their assessment is presented based on key concepts applied in pain research. This theoretical framework assumes that although pain may be localized in one region of the body, the mechanisms causing pain may occur at any level of the somatosensory neuro-axis. Detailed assessment of pain complaints and somatosensory abnormalities should, therefore, be a key element in clinical PSSP research. Studies aiming to further characterize somatosensory functions in patients with PSSP (initially) need to take a broad methodological approach including both clinical as well as more experimental pain research tools, such as quantitative sensory testing. A better understanding of pain mechanisms may explain why persistent PSSP and unsatisfactory pain relief are common despite active prevention and treatment strategies and may provide a basis for improved clinical management of PSSP.