Depression is a common finding after an acute stroke and often interferes with the ability of the patient to participate in the rehabilitation process. A literature review was conducted to investigate the potential benefit of the early administration of antidepressant medication on the rate of depression after acute stroke. Current practices for screening and diagnosing post-stroke depression (PSD) were also reviewed. MEDLINE, CINAHL, Cochrane Library databases, and PsychInfo were searched for relevant articles published in English up to August 2012. One of the challenges identified was that although several studies suggest benefit to the addition of antidepressant medication, little consistency exists in the timing of the intervention, particularly in regards to rehabilitation. Although patients reporting fewer depressive symptoms have been shown to have higher levels of participation in post-stroke therapy, conclusions regarding the benefit of early intervention cannot be made at this time. However, several studies do suggest that, in addition to the benefit of treating PSD, different classes of antidepressant medication may actually facilitate the neural mechanisms of recovery in patients with stroke. Overall, although the current available research cannot recommend the routine administration of antidepressant medication for PSD, the current research can support the administration of this pharmaceutical intervention on an individual basis. Future research needs surrounding PSD are vast, and several questions need to be addressed before focusing on the timing and benefit of early intervention including developing a universally validated screening tool, developing a definitive definition, and establishing acceptable treatment recommendations. Once these topics are further explored, the potential for antidepressants to improve neural mechanisms of recovery can also be further investigated.