Author Summary Typhoid fever is a major cause of disease and death around the world, particularly in resource limited settings, although reports suggest that until recently it has been much less prominent in sub-Saharan Africa (SSA) than Asia. Estimates of the precise burden of this disease are, however, difficult, as diagnosis requires advanced laboratory diagnostics. This is a particular problem in much of SSA where long-term laboratory surveillance has been available in just a few settings. Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi is one such setting; between 1998 and 2010, cases of Typhoid fever at QECH were both uncommon and responsive to all antibiotics. In 2011 a marked increase in highly antibiotic resistant Typhoid fever began, with 843 confirmed cases in 2013. A review of cases revealed that one in 40 patients died and one in five had complicated disease. A further study of the DNA of bacteria associated with the outbreak revealed a novel strain, common to Asia, has arrived in Malawi. This is one of a number of reports of the re-emergence of Typhoid fever in Southern and Eastern Africa. There is an urgent need to understand the reservoirs and transmission of disease and how to arrest this regional increase.