The liver is the largest glandular organ in the body and has a unique distribution of cells and biomolecules. However, the treatment outcome of end-stage liver disease is extremely poor. Single-cell sequencing is a new advanced and powerful technique for identifying rare cell populations and biomolecules by analyzing the characteristics of gene expression between individual cells. These cells and biomolecules might be used as potential targets for immunotherapy of liver diseases and contribute to the development of precise individualized treatment. Compared to whole-tissue RNA sequencing, single-cell RNA sequencing (scRNA-seq) or other single-cell histological techniques have solved the problem of cell population heterogeneity and characterize molecular changes associated with liver diseases with higher accuracy and resolution. In this review, we comprehensively summarized single-cell approaches including transcriptomic, spatial transcriptomic, immunomic, proteomic, epigenomic, and multiomic technologies, and described their application in liver physiology and pathology. We also discussed advanced techniques and recent studies in the field of single-cell; our review might provide new insights into the pathophysiological mechanisms of the liver to achieve precise and individualized treatment of liver diseases.