Substance use disorders (SUDs), including those for alcohol, stimulants, tobacco, opioids and cannabis, in patients with bipolar disorder are a major clinical and public health problem, and are present in the majority of these patients. Nonetheless, the development of effective pharmacological treatments for co-occurring SUDs in bipolar illness have not been well-developed and may be an important practical reason for the reduced effectiveness of these medications in community practice. We conducted a systematic review of the literature (PubMed, Medline, Google Scholar), and identified N = 29 clinical studies, which evaluated both mental health and SUD outcomes in patients with co-occurring bipolar disorders and SUDs. Our findings suggest the potential of valproate sodium and lamotrigine as preferred pharmacological agents for the treatment of co-occurring psychiatric and substance use outcomes in these patients. However, many of the reviewed studies are of open-label designs and of modest sample sizes. Thus, given the gaps in our knowledge, recommendations for treatment of this common and important co-morbidity are preliminary. Accordingly, the conduct of larger, randomized controlled trials for this co-morbidity is clearly needed. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.