The Kilifi Health and Demographic Surveillance System (KHDSS) is a population-based research platform. It was established in the year 2000 to capture vital events and migration among 300,000 residents within an area of 900km2 and is linked to morbidity and mortality surveillance at Kilifi County Hospital. KHDSS provides an epidemiological sampling frame that has allowed us to define the incidence of common childhood infectious diseases (e.g. rotavirus diarrhoea, pneumococcal disease), the association between genetic risk factors (e.g. thalassaemia and sickle cell disease) and infectious diseases, the community prevalence of chronic diseases (e.g. epilepsy), and the operational effectiveness of major public health interventions (e.g. conjugate pneumococcal and Haemophilus influenzae type b vaccines). It has also allowed us to study access to health care and the impact of health worker strikes on health outcomes at population level, and excess mortality during the COVID-19 pandemic.