Background and objectives Epidemiological and immunological studies are increasingly reporting non-specific effects (NSEs) of vaccines; i.e. vaccines may affect the risk and severity of non-targeted infections. We reviewed how epidemiological studies developed the concept of beneficial NSEs of live vaccines. Sources This is a personal narrative of how we came to pursue the concept of NSEs in studies of measles vaccine (MV) from the late 1970s. We also searched Pubmed for epidemiological studies of non-specific/nonspecific effects (NSEs) of the most common human vaccines. Content When smallpox vaccine was introduced around 1800, BCG against tuberculosis in the 1920s and oral polio vaccine (OPV) in the 1960s, there were suggestions that these live attenuated vaccines reduced mortality more than expected. However, scientific follow-up was limited and the concept of beneficial NSEs did not become mainstream. We observed beneficial NSEs after MV was introduced in low-income countries in the 1970s. Subsequent observational studies and randomised trials confirmed beneficial NSEs of smallpox vaccine, BCG and OPV. Recently, beneficial NSEs have been claimed for the non-live diphtheria-tetanus-pertussis and rabies vaccines. However, no non-live vaccine has yet been documented to produce beneficial NSEs. Implications Observational and experimental research has shown beneficial NSEs of four live attenuated vaccines, smallpox vaccine, BCG, OPV and MV. With immunological evidence now supporting the epidemiological observations, it is urgent to take both the specific and NSEs into account in the planning of vaccination programs.