This article is based on a talk given at the Japanese Society for Tropical medicine Annual Meeting in 2014. The severe febrile illness study was established in 2005. The aim of the project was to define the aetiology of febrile disease in children admitted to a hospital in Tanzania. Challenges arose in many areas: Study design: An initial plan to recruit only the severely ill was revised to enroll all febrile admissions leading to a more comprehensive dataset but much increased costs. Operationally a decision was made to set up a paediatric acute admissions unit (PAAU) in the hospital to facilitate recruitment and to provide appropriate initial care in line with perceived ethical obligations. This had knock on effects relating to the responsibilities that were taken on but also some unexpected positive outcomes. Study personnel: Local research staff were sometimes called upon to make up temporary shortfalls in the hospital staffing. Lack of staff made it impossible to recruit patients around the clock, seven days a week creating the challenge of ensuring representative sampling. Quality control: Studies based on clinical examination create unique quality control challenges—how to ensure that clinical staff are examining in a systematic and reproducible way. We designed a sub-study to both explore this and improve quality. Summary: Setting up clinical research projects is severely resource poor settings creates many challenges including those of an operational, technical and ethical nature. Whilst there are no ‘right answers’ an awareness of these problems can help overcome them.