Delirium is the most frequent manifestation of acute brain dysfunction in intensive care unit (ICU). Although antipsychotics are widely used to treat this serious complication, recent evidence has emphasized that these agents did not reduce ICU delirium (ICU-D) prevalence and did not improve survival, length of ICU or hospital stay after its occurrence. Of note, no pharmacological strategy to prevent or treat delirium has been identified, so far. In this scenario, new scientific evidences are urgently needed. Investigations on specific ICU-D subgroups, or focused on different clinical settings, and studies on medications other than antipsychotics, such as dexmedetomidine or melatonin, may represent interesting fields of research. In the meantime, because there is some evidence that ICU-D can be effectively prevented, the literature suggests strengthening all the strategies aimed at prevention through no-pharmacological approaches mostly focused on the correction of risk factors. The more appropriate strategy useful to treat established delirium remains the use of antipsychotics managed by choosing the right doses after a careful case-by-case analysis. While the evidence regarding the use of dexmedetomidine is still conflicting and sparse, this drug offers interesting perspectives for both ICU-D prevention and treatment. This paper aims to provide an overview of current pharmacological approaches of evidence-based medicine practice. The state of the art of the on-going clinical research on the topic and perspectives for future research are also addressed.