Cassava is a major food crop in Africa and Asia. Cassava can grow under drought, high temperature and poor soil conditions, but its production is severely limited by viral diseases. Cassava Mosaic Disease (CMD) is one of the most economically important crop diseases in Africa. CMD induces severe stunting and a yellow mosaic pattern due to disruption of chloroplast function, which results in reduced tuber size and yield loss. During the recent pandemic that spread across Sub-Saharan Africa in the 1990s and 2000s, CMD was associated with a 47% yield loss in East and Central Africa. Cassava is a vegetatively propagated crop. Limited availability of virus-free explants is a major challenge for cassava production in Africa, and many farmers do not have access to “clean” planting materials. Hence, they often start with stakes from virus-infected plants, and the infected progeny develop symptoms throughout the leaf canopy from the beginning of the growing season. CMD is also transmitted by whiteflies from infected plants to healthy plants. In this case, symptoms can emerge anytime during the growing season and develop above the feeding site on the plant. Vegetative propagation and whitefly transmission of CMD may impact virus evolution differently. No studies have systematically evaluated the effects of vegetative propagation, whitefly transmission, and the environment to understand the drivers of viral genetic diversity, emergence, persistence and spread. We propose such a comprehensive study taking an experimental evolution approach using defined viral inoculum, standardized inoculation protocols and plants grown under uniform environmental conditions.