Several studies demonstrated that repetitive transcranial magnetic stimulation (rTMS) is an efficacious treatment for treatment-resistant major depressive disorder (TRD). Recent metaanalyses and more recent large multicentre studies provided evidence suggesting that rTMS is indeed a promising treatment; however, its efficacy has often been shown to be modest, compared with sham stimulation. We review these lines of evidence and discuss several reasons that may explain the modest therapeutic efficacy in most of these studies, including: most involved left-sided treatment alone to the dorsolateral prefrontal cortex (DLPFC) only, which may be less optimal than applying bilateral stimulation; suboptimal methods were used to target the DLPFC (that is, the 5-cm anterior method), limiting the treatment potential of inherently a targeted form of treatment; some treatment durations were short (that is, 2 to 4 weeks); and stimulation intensity might have been insufficient by not considering coil-to-cortex distance, which has been linked to rTMS-induced antidepressant response. Future studies attempting to address the above-mentioned limitations are necessary to potentially optimize the efficacy of this already promising treatment option in TRD. Finally, it is also essential that research investigate the mechanisms of therapeutic efficacy, thus increases in understanding can be translated into enhanced treatment. For several reasons that will be reviewed, cortical excitability may represent an important mechanism, linked to the therapeutic efficacy of this disorder.