The liver is a major organ with a wide range of functions, including detoxification, protein synthesis, and bile production. Liver dysfunction causes liver diseases such as hepatic cirrhosis and hepatitis. To explore the pathogenesis of these liver diseases, and the therapeutic agents against them, mice have been widely used as animal models. Genetic manipulation is easy in mice via the administration of nucleic acids (NAs) in the tail-vein. In particular, hydrodynamics-based gene delivery (HGD) is a method based on the introduction of a large volume of NA-containing solution over a short period in the tail-vein. It is recognized as a powerful tool to efficiently transfect hepatocytes. Genome editing, as illustrated by the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) (CRISPR/Cas9) system, has also been recognized as a powerful tool to manipulate target genes in host genomes. Recently, studies have described the tail-vein-mediated introduction of genome editing components for the generation of liver tumors, correction of mutated genes causing liver dysfunction, and generation of mice with liver disease. More importantly, this HGD method can bypass the need to create mouse progeny carrying the targeted mutation in their germline. In this review, the past and present achievements of liver-targeted manipulation achieved via intravenous injection of genome editing components will be summarized.