Liver cancer has the highest increase in incidence and mortality of all cancers in the United States in recent decades. A major effort has been taken over the last 10 years to understand molecular heterogeneity between tumors of different patients through the development of mutation signatures and molecular classifications. More recently, attention has shifted to understanding intra-tumor heterogeneity (ITH). Several possibilities exist as to the underlying mechanisms that drive ITH in liver cancer, including cancer stem cells (CSCs) and neutral and clonal evolution. Tracking ITH changes in patients over treatment courses will become imperative as precision medicine comes to the forefront of cancer management. Here we review the models of ITH development in liver cancer and the impact ITH assessment can have on clinical management.