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Heart failure (HF) has been traditionally viewed as a disease of the cardiac muscle associated with systemic inflammation. Burgeoning evidence implicates immune effector mechanisms that include immune cell activation and trafficking to the heart. Immune cell infiltration in the myocardium can have adverse effects in the heart and contribute to the pathogenesis of HF. Both innate and adaptive immunity operate sequentially, and the specificity of these responses depends on the initial trigger sensed by the heart. Although the role of the immune system in the initial inflammatory response to infection and injury is well studied, what sets the trajectory to HF from different etiologies and the role of immunity once HF has been established is less understood. Herein, we review experimental and clinical knowledge of cardiac inflammation induced by different triggers that often result in HF from different etiologies. We focus on the mechanisms of immune cell activation systemically and on the pathways immune cells use to traffic to the heart., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)