Lateral epicondylalgia or tennis elbow is a prevalent musculoskeletal disorder that is characterized by lateral elbow pain often associated with gripping tasks. The underlying pathology remains to be fully elucidated; however, evidence indicates that the disorder does not involve an inflammatory process but rather impairments of the pain and motor systems as well as morphological changes in the structure of both the extensor carpi radialis brevis muscle and tendon. Although the most efficient management approach remains controversial, there is a growing body of literature reporting the effects and underlying mechanisms of joint manipulation in the management of lateral epicondylalgia. Evidence exists demonstrating that joint manipulation directed at the elbow and wrist as well as at the cervical and thoracic spinal regions results in clinical alterations in pain and the motor system. In addition to presenting this evidence, this paper describes proposed underlying physiological mechanisms of joint manipulation associated with the observed clinical effects. We propose that this information will be useful for the physical therapist in making clinical decisions regarding the selection of treatment technique for the management of patients with lateral epicondylalgia.