Acute myocardial infarction (AMI) is a disease associated with high morbidity and mortality. Currently there are no available treatments specifically targeting the post-ischemic myocardial processes that lead to heart failure and recurrent coronary events. The innate immune system plays a central role in the two consecutive phases that follow an acute ischemic event: the inflammatory phase and the reparatory phase. The inflamatory phase involves a massive infiltration of neutrophils and inflammatory Ly6Chi monocytes into the injured myocardium. The reparatory phase is orchestrated by reparatory Ly6Clo macrophages that clear necrotic and apoptotic cells through efferocytosis, secrete anti-inflammatory mediators and stimulate fibrosis and repair. Important recent studies provided proof that Ly6Chi monocytes that enter the myocardium in the inflammatory phase upregulate the orphan nuclear receptor Nr4a1 and switch phenotype to Ly6CloNr4a1hi reparatory macrophages. Additionally, neutrophils have been shown to promote cardiac recovery by upregulating expression of the efferocytosis receptor MerTK on reparatory macrophages. A finely tuned balance between the inflammatory and the reparatory phases is thus essential for limiting myocardial damage and promoting efficient recovery. Treatment strategies targeting only the inflammatory phase have so far failed to improve prognosis in AMI patients. A detailed understanding of the interplay between the two phases of the innate immune response is paramount for designing efficient therapies able to improve post- AMI prognosis. In the current review, we summarize the state-of-the-art of the field and discuss previous therapeutic attempts and currently ongoing clinical trials targeting innate immune mechanisms in AMI patients.