Acute myocardial infarction (AMI) is a leading cause of heart failure and premature death worldwide [1]. Both immediate medical treatment and rapid reperfusion to limit myocardial damage are strongly recommended [2, 3]. However, reperfusion has the potential to initiate additional lethal injury, known as ‘ischemia–reperfusion (IR) injury,’ and could result in increased cardiac cell death [4]. New therapeutic strategies that directly target the reperfusionmediated damage have been proved to reduce infarct size (IS) in experimental animal models. These approaches include (1) ischemic postconditioning [5, 6] and even remote postconditioning [7]; (2) pharmacological postconditioning including cyclosporine A [8] or normalization of intracellular calcium homeostasis [9, 10]; and (3) genetic perturbation in animal models of critical proapoptotic pathways involved in reperfusion injury [11, 12]. These new approaches have been shown to improve ventricular remodeling and clinical outcomes after AMI [13–17]. IR lesions are partly mediated and worsened by oxidative stress [18]. One of the most known anti-oxidative agents is N-acetylcysteine (NAC), but results in clinical translation have been most often disappointing as regards cardiovascular disease [19] as well as nephrology [20]. Nevertheless, NAC is currently under study in various fields of medical research, as briefly presented in the Table 1, noticeably in psychiatry disorders. This venerable drug had been already proposed as an interesting candidate for cardioprotection for decades [21–24], but controversial results have been obtained. In this issue of the Journal, Talasaz et al. [25] once again address the efficacy of NAC to control post-MI remodeling. They suggest that NAC could improve the myocardial remodeling following AMI in a proof-ofconcept clinical trial. In this prospective, double-blinded, randomized clinical trial, 98 patients were allocated to placebo or NAC at the dose of 600 mg orally twice daily during three days upon hospital arrival. The authors showed that serum levels of metalloproteinase (MMP)-9 and MMP-2 after 72 h and major adverse cardiac events including re-infarction during the 1-year follow-up were significantly lower in the treated group than in the placebo group. However, several limitations have to be underlined, and this proof-of-concept trial has to be confirmed in larger trials. Among the limitations, mainly biochemical and baseline echographic parameters have been considered, so it is difficult to conclude on echocardiographic evolution, IS (whether this was accurately measured) or specific clinical outcomes. Reperfusion is not always obtained (only 40 % of the patients received primary coronary intervention), collateral flow or area at risk are not taken into consideration, and, importantly, the sample is small. Whether the design of the study, especially the timing (as soon as possible to treat the IR lesions), the route (would intravenous/intracoronary route, if safe, be more efficient?), and the very drug under study, including This paper is a commentary on the original paper at doi:10.1007/s40256-013-0048-x.