Human monocytic ehrlichiosis, a tick transmitted infection, ranges in severity from apparently subclinical to a fatal toxic shock-like fatal disease. Models in immunocompetent mice range from an abortive infection to uniformly lethal depending on the infecting Ehrlichia species, dose of inoculum, and route of inoculation. Effective immunity is mediated by CD4+ T lymphocytes and gamma interferon. Lethal infection occurs with early overproduction of proinflammatory cytokines and overproduction of TNF alpha and IL-10 by CD8+ T lymphocytes. Furthermore, fatal ehrlichiosis is associated with signaling via TLR 9/MyD88 with upregulation of several inflammasome complexes and secretion of IL-1 beta, IL-1 alpha, and IL-18 by hepatic mononuclear cells, suggesting activation of canonical and noncanonical inflammasome pathways, a deleterious role for IL-18, and the protective role for caspase 1. Autophagy promotes ehrlichial infection, and MyD88 signaling hinders ehrlichial infection by inhibiting autophagy induction and flux. Activation of caspase 11 during infection of hepatocytes by the lethal ehrlichial species after interferon alpha receptor signaling results in the production of inflammasome-dependent IL-1 beta, extracellular secretion of HMGB1, and pyroptosis. The high level of HMGB1 in lethal ehrlichiosis suggests a role in toxic shock. Studies of primary bone marrow-derived macrophages infected by highly avirulent or mildly avirulent ehrlichiae reveal divergent M1 and M2 macrophage polarization that links with generation of pathogenic CD8 T cells, neutrophils, and excessive inflammation or with strong expansion of protective Th1 and NKT cells, resolution of inflammation and clearance of infection, respectively.