Personalized medicine and health care reform offer the opportunity for pathologists to have a more central and visible role in patient care. Pathologists face new and more complicated requests for clinical and research testing on tissue specimens, including testing for somatic and inherited mutations. Pathologists must comprehend the applications and requirements for molecular testing and their legal and ethical responsibilities in handling tissue requests for clinical and research purposes to best serve the needs of patients and clinicians and to comply with federal and state laws. This article reviews these rapidly evolving and complex areas.