Over the past 324 years, Charleston, South Carolina, has triumphed over rampant infectious disease only to be overcome by more modern plagues: heart disease, neoplasia, homicide, and suicide. Examination of death records of the state of South Carolina, Charleston City, and Charleston County provides us with a glimpse of the medical challenges of our recent past; it also reminds us of the scourges that still ravage underdeveloped countries. The 18th- and 19th-century South Carolinians were besieged by tuberculosis, diarrhea, and a myriad of fevers. These diseases, though prevalent in other parts of the world, result in limited mortality in the 20th-century United States. A review of the historic trends in mortality in Charleston is presented; current significant causes of death, with emphasis on recent trends in homicide, are also discussed.