The cutaneous surface, nails, hair, and oral cavity often afford clues to many underlying disorders. The skin is sometimes referred to as a “window to disease.” For example, the presence of jaundice, palmar erythema, pruritus, and spider telangiectasias point to liver disease. The appearance of pyoderma gangrenosum, erythema nodosum, or severe aphthous stomatitis may indicate inflammatory bowel disease. By appreciating skin signs of systemic diseases, the healthcare provider can often lead his or her patient to an early diagnosis and appropriate treatment. This chapter reviews some of the cutaneous manifestations of systemic diseases and highlights some of the recent developments in their management.