The defining symptom, and often the major reason for seeking medical treatment associated with most clinical disorders of the hand and wrist, is pain. However, pain mechanisms following MSK trauma are complex, multifactorial, and remain largely unknown.As such, this thesis sought to understand pain mechanisms in hand and wrist MSK pathologies, using imaging-based biomarkers and gold-standard pain evaluation techniques. Chapter 2 presents an exploratory analysis on the interacting influences of sex on multi-modal pain evaluation techniques that tap different pain domains. Our results highlight the importance of multiple pain measures when creating sex-specific intervention strategies, as the accuracy of predicting ones’ clinical pain evaluation scores did not show true difference greater than chance. Chapter 3 explores the use of imaging-based biomarkers, namely subchondral volumetric bone mineral density (vBMD) and static joint contact area (JCA), to differentiate between two study cohorts. On average, our healthy cohort had a higher vBMD for all measured depths from the subchondral surface of the distal radius. Chapter 4 presents the relationship between subchondral vBMD and kinematic JCA throughout a range of motion in a healthy cohort of adults to understand the impact of joint contact on subchondral bone. In deep regions of subchondral bone, a higher vBMD was significantly correlated to a larger JCA, most notably during wrist extension. Lastly, Chapter 5 explores the preliminary association between structural and clinical disease progression, using pain evaluation measures and our imaging-based biomarkers, in a cohort of thumb carpometacarpal osteoarthritis (CMC OA) patients. Our preliminary results demonstrated that structural severity was significantly associated with a higher pain score and pain presentation was heterogeneous.