The excitement surrounding immuno-oncology (I-O) is being driven by results seen in the clinic, mainly over the last five years, following the approval of the immune checkpoint inhibitor, Yervoy® (ipilimumab), an anti-CTLA-4 antibody. Development of such immuno-therapeutics has resulted in significantly improved clinical outcomes for some patients suffering from serious cancers. Despite these successes, very little is known about prognostic or therapeutic biomarkers to help identify people who could receive these benefits. Genomics can additionally empower the success of these therapies by developing associated biomarkers to identify patients likely to experience the best efficacy, while potentially reducing toxicities and adverse events. Identifying which patients are likely to obtain these benefits can be greatly accelerated by using high-throughput sequencing (HTS) technology, which has already demonstrated great promise in targeted therapy approaches. In this white paper we summarize the clinical relevance of RNA-Seq as well as when and how to use expression profiling for biomarker discovery for immunotherapy trials.