Infective endocarditis (IE) incidence remains high with considerable fatality rates; guidelines for prophylaxis against IE are currently under review in some settings which highlights the importance of maintaining up-to-date epidemiological estimates about the most common microbial causes. The objective of this systematic review, following PRISMA guidelines, was to identify the most common microbial causes of IE in recent years. Medline was searched from January 1, 2003 to March 31, 2013 for all articles containing the term "infective endocarditis". All relevant studies reporting diagnostic results were included. Special patient subpopulations were assessed separately. A total of 105 studies were included, from 36 countries, with available data on a total of 33,214 cases. Staphylococcus aureus was found to be the most common microorganism, being the most frequent in 54.3 % of studies (N = 57) (and in 55.4 % of studies using Duke's criteria for diagnosis [N = 51]). Viridans group streptococci (VGS), coagulase-negative staphylococci (CoNS), Enterococcus spp and Streptococcus bovis were among the most common causes. S. aureus was the most common pathogen in almost all population subgroups; however, this was not the case in patients with implantable devices, prosthetic valves, or immunocompromised non-HIV, as well as in the sub-group from Asia, emphasizing that a global one-size-fits-all approach to the management of suspected IE is not appropriate. This review provides an evidence-based map of the most common causative agents of IE, highlighting S. aureus as the leading cause in the 21st century. The changing epidemiology of IE in some patient sub-groups in the last decade and the very high number of microbiologically undiagnosed cases (26.6 %) suggest the need to revisit IE prophylaxis and diagnostic strategies.