Background: Eye movement desensitization and reprocessing [EMDR] is an innovative, evidence-based and effective psychotherapy for post-traumatic stress disorder [PTSD]. As with other psychotherapies, the effectiveness of EMDR contrasts with a limited knowledge of its underlying mechanism of action. In its relatively short life as a therapeutic option, EMDR has not been without controversy, in particular regarding the role of the bilateral stimulation as an active component of the therapy. The high prevalence of EMDR in clinical practice and the dramatic increase in EMDR research in recent years, with more than 26 randomized controlled trials published to date, highlight the need for a better understanding of its mechanism of action. Methods: We conducted a thorough systematic search of studies published until January 2018, using PubMed, ScienceDirect, Web of Knowledge and Scopus databases that examined the mechanism of action of EMDR or provided conclusions within the framework of current theoretical models of EMDR functioning. Results: Eighty-seven studies were selected for review and classified into three overarching models; (i) psychological models (ii) psychophysiological models and (iii) neurobiological models. The evidence available from each study was analyzed and discussed. Results demonstrated a reasonable empirical support for the working memory hypothesis and for the physiological changes associated with successful EMDR therapy. Recently, more sophisticated structural and functional neuroimaging studies using high resolution structural and temporal techniques are starting to provide preliminary evidence into the neuronal correlates before, during and after EMDR therapy. Discussion: Despite the increasing number of studies that published in recent years, the research into the mechanisms underlying EDMR therapy is still in its infancy. Studies in well-defined clinical and non-clinical populations, larger sample sizes and tighter methodological control are further needed in order to establish firm conclusions.