A growing body of evidence from epidemiologic, clinical, and immunologic studies indicates that vaccines can influence morbidity and mortality independent of vaccine-specific B-cell or T-cell immunity. For example, the live attenuated measles vaccine and BCG vaccine may reduce mortality from infections other than measles or tuberculosis, respectively. Immunologists call these heterologous effects and epidemiologists have called them nonspecific effects, indicating that they manifest against a broad range of pathogens/disease. These effects differ by sex, can be beneficial or detrimental, and appear to be mediated by mechanisms including innate immune memory (also known as trained immunity ) and cross-reacting lymphocytes. Herein we review recent studies in this emerging field based on a meeting of experts, the recent Optimmunize meeting, held in Copenhagen, Denmark, in August 2012. Further characterization of these effects is likely to expand the way vaccines are evaluated and alter the manner and sequence in which they are given. ? 2013 The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.