The century-old tuberculosis vaccine BCG has been the focus of renewed interest due to its well-documented ability to protect against various non-TB pathogens. Much of these broad spectrum protective effects are attributed to trained immunity, the epigenetic and metabolic reprogramming of innate immune cells. As BCG vaccine is safe, cheap, widely available, amendable to use as a recombinant vector, and immunogenic, it has immense potential for use as an immunotherapeutic agent for various conditions including autoimmune, allergic, neurodegenerative, and neoplastic diseases as well as a preventive measure against infectious agents. Of particular interest is the use of BCG vaccination to counteract the increasing prevalence of autoimmune and allergic conditions in industrialized countries attributable to reduced infectious burden as described by the 'hygiene hypothesis.' Furthermore, BCG vaccination has been proposed as a potential therapy to mitigate spread and disease burden of COVID-19 as a bridge to development of a specific vaccine and recombinant BCG expression vectors may prove useful for the introduction of SARS-CoV-2 antigens (rBCG-SARS-CoV-2) to induce long-term immunity. Understanding the immunomodulatory effects of BCG vaccine in these disease contexts is therefore critical. To that end, we review here BCG-induced immunomodulation focusing specifically on BCG-induced trained immunity and how it relates to the 'hygiene hypothesis' and COVID-19. Copyright © 2020 Elsevier GmbH. All rights reserved.