Though all genes exist within every cell in the human body, only a defined gene expression program is executed at any time via reprogramming of the epigenome in response to environmental cues. These dynamic events are elegantly orchestrated by writer and eraser enzymes; generating a ‘histone code’ within the epigenetic landscape of genes.  The implications of targeting a novel class of epigenetic enzymes, nuclear signalling kinases, are beginning to be appreciated in clinical oncology. In this seminar, I will present my laboratory’s recent focus on immune-oncology in metastatic breast cancer and advanced melanoma. I will also discuss our development of novel classes of liquid biopsy based biomarkers and companion epi-inhibitors as well as potential implications for the utility of epi-therapy in combination with immunotherapy and chemotherapy. Finally, I will present our novel single cell epigenetic tools for FFPE analysis from patient derived tissue biopsies.