Background: Data on the burden of severe Staphylococcus aureus disease, a significant cause of invasive bacterial infections among children aged <5 years in The Gambia and Africa at large, are lacking. The work in this thesis estimates the burden (cases and deaths) of severe S. aureus disease in Africa, the incidence of S. aureus bacteraemia (SAB) in children aged <5 years and assesses the risk factors for neonatal S. aureus acquisition in rural Gambia. Methods: This thesis includes three separate studies. First, following a systematic literature review and meta-analysis, raw and processed data were synthesised to estimate the numbers of cases and deaths due to severe S. aureus diseases in children aged <5 years in Africa. Second, the incidence and case fatality ratio (CFR) of SAB in <5 years Gambian children were estimated from a population-based study. Lastly, a longitudinal study of newborn-contact pairs was used to evaluate the risk factors associated with neonatal S. aureus carriage at birth as well as with its acquisition at one-week of age. Results: In Africa, an estimated 392,066 cases and 46,467 deaths due to severe S. aureus disease occurred among children aged <5 years with 20.4% and 58.4% of these occurring among neonates, respectively in 2015. The incidence of SAB among Gambian children aged <5 years and neonates was 78/100,000 person-years (95%CI 67–91) and 3.5/1,000 live-births (95%CI 2.9–4.7), respectively. The CFR was 14.1% (95%CI 9.6-19.8). S. aureus carriage at birth was associated with the midwife’s report of handwashing before delivery while carriage acquisition one week after delivery was associated with maternal and household child nasal carriage. Conclusion: The burden of severe S. aureus disease among children aged <5 years in Africa is substantial. Developing new, and implementing existing, strategies urgently to tackle this will contribute to achieving the sustainable development goals.