Adult stem cell plasticity raised expectations regarding novel cellular therapies of regenerative medicine after findings of unexpected plasticity were reported. In this review, reports of hematopoietic stem cells (HSCs) contributing to hepatocytic lineages are critically discussed with reference to rodent and human models. In particular, the role of liver injury and the potential contribution HSCs make to hepatic regeneration in both injury and physiological maintenance is reviewed. The relative contributions of genomic plasticity and cell fusion are studied across different model systems, highlighting possible factors that may explain differences between often conflicting reports. Insights from experimental studies will be described that shed light on the mechanisms underlying the migration, engraftment, and transdifferentiation of HSCs in liver injury. Although it appears that under differing circumstances, macrophage fusion, HSC fusion, and HSC transdifferentiation can all contribute to hepatic epithelial lineages, a much greater understanding of the factors that regulate the long-term efficacy of such cells is needed before this phenomenon can be used clinically.