The host immune response is a potent defense mechanism against cancer development and progression. To survive, cancer cells must develop mechanisms to evade the immune response. Based on this knowledge, a series of new therapies collectively referred to as immunotherapies have been developed and translated to the clinic for treating cancer patients. Although some cancer subtypes have shown strong clinical responses, including curative outcomes in some patients, immunotherapies have not worked as desired for some subtypes and forms of cancers. We provide an overview of the transcriptional mechanisms that drive the response and resistance to immunotherapies. We also discuss possible interventions to enhance the outcomes of immunotherapies by targeting dysregulated transcriptional networks in cancer cells.