Immuno-oncology therapies are revolutionizing the oncology landscape with checkpoint blockade becoming the treatment backbone for many indications. While inspiring, much work remains to increase the number of cancer patients that can benefit from these treatments. Thus, a new era of immuno-oncology research has begun which is focused on identifying novel combination regimes that lead to improved response rates. This review highlights the significance of small molecules in this approach and illustrates the huge progress that has been made to date.