Cancer patients with receiving chemotherapy and targeted therapy have persistent cancer cells remaining in their bodies. These cells are labelled by their slow proliferation, high metabolic plasticity, high phenotypic plasticity, and strong adaptability to the tumor microenvironment. The molecular mechanisms of these characteristics promote the development of drug resistance in persistent cancer cells. The slow proliferation mechanism of persistent cancer cells can occur intracellularly or be triggered by microenvironment. Cell metabolism is regulated by mitochondrial respiration, protein synthesis, and antioxidant pathways in persistent cancer cells. The phenotype of persistent cancer cells is changed by epithelial-to-mesenchymal transition and transdifferentiation. Tumor-associated macrophages, cancer-associated fibroblasts and other cells in the microenvironment interact with persistent cancer cells to enhance their adaptability to the microenvironment. At the present clinical situation, the development of a reliable preclinical cancer models is of great significance to further study the characteristics of persistent cancer cells so that new clinical strategies targeting persistent cancer cells for doctors to carry out.