Data from several laboratories have shown that ethanol (EtOH) feeding impairs many essential methylation reactions that contribute to alcoholic liver disease (ALD). EtOH is also a comorbid factor in the severity of hepatitis C virus–induced liver injury. The presence of viral proteins further exacerbates the methylation defects to disrupt multiple pathways that promote the pathogenesis of liver disease. This review is a compilation of presentations that linked the methylation reaction defects with proteasome inhibition, decreased antigen presentation, and impaired interferon (IFN) signaling in the hepatocytes and dysregulated TNFα expression in macrophages. Two therapeutic modalities, betaine and S-adenosylmethionine, can correct methylation defects to attenuate many EtOH-induced liver changes, as well as improve IFN signaling pathways, thereby overcoming viral treatment resistance.