Johne’s disease (JD), also known as paratuberculosis, is a severe production-limiting disease with significant economic and welfare implications for the global cattle industry. Caused by infection with Mycobacterium avium subspecies paratuberculosis (MAP), JD is manifested as chronic enteritis in infected cattle. In addition to the economic losses and animal welfare issues associated with JD, MAP has attracted public health concerns with potential association with Crohn’s disease, a human inflammatory bowel disease. The lack of effective treatment options, such as a vaccine, has hampered JD control resulting in its increasing global prevalence. The disease was first reported in 1895, but in recognition of its growing economic impact, extensive recent research facilitated by a revolution in technological approaches has led to significantly enhanced understanding of the immunological, genetic, and pathogen factors influencing disease pathogenesis. This knowledge has been derived from a variety of diverse models to elucidate host-pathogen interactions including in vivo and in vitro experimental infection models, studies measuring immune parameters in naturally-infected animals, and by studies conducted at the population level to enable the estimation of genetic parameters, and the identification of genetic markers and quantitative trait loci (QTL) putatively associated with susceptibility or resistance to JD. The main objectives of this review are to summarize these recent developments from an immunogenetics perspective and attempt to extract the principal and common findings emerging from this wealth of recent information. Based on these analyses, and in light of emerging technologies such as gene-editing, we conclude by discussing potential avenues for effectively mitigating JD in cattle.