In recent years, emphasis on the physical examination has made way for a plethora of laboratory tests and sophisticated imaging diagnostic techniques. In addition, we are witnessing an underestimation of dermatology as a specialty around the world, which is accepted as an ambulatory specialty on the border of cosmetology and beautification. However, recognizing specific cutaneous clinical signs can facilitate timely diagnosis of various systemic infections and neoplastic diseases. Thus, a skilled dermatologist can play an essential role in the multidisciplinary team, involved in the care for systemically ill patients. In this article, we will focus on some life threatening systemic infections in which the skin changes can be a major clue for the diagnosis. Recent deadly epidemics will also be focused. Classic examples of paraneoplastic skin conditions will also be provided.