Multiple clinical trials have been performed to test the hypothesis that administration of bone-marrow-derived progenitor and stem cells (BMCs) may improve left-ventricular (LV) function following acute myocardial infarction (AMI). These studies have generally confirmed that cell therapy administration can be safely administered; however, consensus has not been reached on whether this approach results in an improvement in LV function or clinical outcomes. Although many of the published studies have been randomized, placebo-controlled trials, many important questions regarding patient selection, methodology and trial design still exist. To date, almost no information has been obtained in regard to optimal dosing and cell type, timing of administration and preferred method of delivery. As a result, current cell therapy administration for AMI finds itself at the crossroads. In this review we have highlighted some of the important questions that remain unanswered in the field of cell therapy after AMI. We believe that future cell therapy trials should attempt to incorporate these important issues in designing upcoming clinical trials in order for the field to move forward.