Drug Induced Liver Injury (DILI) is a major contributor to the overall clinical occurrence of acute liver failure (ALF), often leading to early termination of clinical trials, post-marketing drug withdrawals, and the need for liver transplantation, and compound-specific causality is not always clear. Despite a recent pivot toward utilization of in vitro tools for early safety assessment, nonclinical safety studies are still utilized to predict clinical liabilities for new drugs. However, recent advancements in genome editing coupled with network-based approaches in toxicogenomics allow new insight to explore relationships from molecular/cellular level to pathological changes occurring at the organ in preclinical studies. Here, we will focus on recent investigations utilizing an integrated systems biology toolkit consisting of CRISPR/Cas9 and toxicogenomics to reduce uncertainty for both adaptive and progressive changes in the liver during early safety assessment as well as implications for new therapeutics.