Migration has deep historical roots in South and Southern Africa and to this day continues to be highly prevalent and a major factor shaping South African society and health. In this paper we examine the role of migration in the spread of two diseases nearly 100 years apart: tuberculosis following the discovery of gold in 1886 and HIV in the early 1990s. Both cases demonstrate the critical role played by human migration in the transmission and subsequent dissemination of these diseases to rural areas. In both cases, migration acts to assemble in one high-risk environment thousands of young men highly susceptible to new diseases. With poor living and working conditions, these migration destinations act as hot-spots for disease transmission. Migration of workers back to rural areas then serves as a highly efficient means of disseminating these diseases to rural populations. We conclude by raising some more recent questions examining the current role of migration in Southern Africa.