The ability of the hepatitis B virus X protein to interact with and alter host transcription factors, thereby deregulating cellular gene expression is thought to be a key mechanism by which the virus contributes to hepatocellular carcinoma. Research over the last two decades has yielded a growing list of such transcription regulators, but their intricate interplay in the presence of HBx in the complex network of mammalian transcription regulation remains less understood. Here we will provide an overview of the current knowledge of HBx modulation of biologically relevant transcription factors and its deregulated gene targets, contributing to carcinogenesis. Importantly, we will discuss recent approaches leveraging on the application and integration of global profiling technology including chromatin immunoprecipitation-sequencing and gene expression microarray that would provide greater biological insights to the modulation of the complex transcription network by HBx.