Acute rejection (AR) seems to be less common with current immunosuppressive strategies; however, it remains a major cause of morbidity and mortality in the first year following heart transplantation. Despite great interest in noninvasive methods for detecting rejection, the endomyocardial biopsy remains the standard method for AR identification and, recently, the cardiac biopsy grading system has been reviewed. Moreover, the availability of several immunosuppressive drug combinations has generated confusion in the minds of clinicians. This review will focus on recently published studies that are related to the clinical impact of AR, combination regimens of chronic maintenance immunosuppression and specific therapeutic options for treating AR.