Several data suggest an association between repeated psychotic episodes in patients with schizophrenia and poor outcomes on the course of the illness, including worse psychosocial functioning and quality of life, deterioration and stigma. However, there is strong evidence showing antipsychotic efficacy for relapse prevention in chronic and first-episode patients. Non-adherence and partial adherence to antipsychotic treatment is a common feature that has been detected in half or more patients with schizophrenia. The use of long-acting injectable antipsychotics (LAIs) is a valuable treatment option in order to prevent non-adherence rates and the risk of relapse in patients with schizophrenia. Nevertheless, LAIs are an underutilized, yet efficacious, treatment option. This underutilization is due, at least in part, to patients and clinicians reluctance to use LAIs because of needle pain, time constraints, stigmatization, and cost. However, results from recent meta-analytic evidences including randomized control trials (RCTs) are in contrast with those from naturalistic cohort studies or mirror-image studies in showing superiority of LAIs versus oral antipsychotics (OAPs) in preventing relapse in patients with schizophrenia. After a review of updated data, guidance will be offered concerning the appropriate use of LAIs in patients with schizophrenia.