Acquired Aplastic Anemia (AA) is a rare immune-mediated disorder characterized by peripheral blood cytopenias resulting from a hypocellular marrow. Significant advances have been made to characterize the dysregulated immune system and responses to understand the pathogenesis of AA, which in turn have unraveled the genetic predisposition markers (host) and the causal role of environmental factors, and more importantly, the interplay between them in a proportion of these cases. National registries and retrospective studies have identified a marked variation in disease incidence among certain ethnic populations and geographical regions where polymorphism for various Human leukocyte antigen (HLA) alleles has subsequently been found. Idiosyncratic reaction of the bone marrow to certain drugs and toxins has led to better pharmacovigilance practices, better monitoring, and the judicious use of these agents in clinical practice. AA following viral infections, including post-hepatitis AA, other autoimmune disorders, pregnancy, and following vaccination, all highlight a disturbed immune milieu in the body toward disease predisposition. Autoimmunity remains at the core of acquired AA, but we highlight important epidemiological influences that give context and a better understanding of the disordered nature of this autoimmune disease.