We provide a brief summary of studies from our laboratory that establish Xist activation or repression by impairment or loss of tumor suppressor function, control of Xist by DNA damage and repair pathways, establish the Xist non-coding RNA as an epigenetic modulator of autosomal gene expression, identify the existence of an Xist RNP complex that functions in normal and transformed cellular contexts, and describe physiologically relevant functions of Xist in human cancer: in transformation, in subtype selection, in resistance and response to clinical therapy.