The wound healing response after myocardial infarction (MI) involves a cascade of molecular and cellular events that lead to a replacement of the necrotic area with a collagen-rich scar. Clearance of necrotic debris by neutrophils, monocytes, and macrophages is a critical component of infarct healing; however, tight control and timely repression of this inflammatory response is important to prevent excessive tissue degradation leading to infarct expansion and heart failure. Genetic ablation or blockade of anti-inflammatory pathways tends to be detrimental after MI, whereas genetic ablation of pro-inflammatory pathways tends to be beneficial. Accordingly, therapies enhancing endogenous anti-inflammatory pathways or blocking endogenous pro-inflammatory pathways have been found to improve wound healing and to reduce the risk of heart failure in rodent models of acute MI. Besides their scavenger function, inflammatory cells promote healing by stimulating angiogenesis and granulation tissue formation via paracrine factors. Moreover, signaling mediators that are active in inflammatory cells may be active also in non-inflammatory cell types involved in infarct healing. Some anti-inflammatory interventions are therefore deleterious. However, interventions that carefully adjust the balance between the essential and detrimental facets of inflammation may provide new therapeutic opportunities for patients with large MIs who continue to be at risk of developing heart failure, despite modern reperfusion and anti-remodeling strategies.