Lipid metabolism disorder is the cause of one of the most significant metabolic changes in tumors. In the process of tumor occurrence and development, tumor cells choose a continuous metabolic adaptation to accommodate the changing environment to the maximum extent possible. In a variety of tumors, the uptake, production, and storage of lipids are generally upregulated. Tumor cells take advantage of lipid metabolism to access basic energy, biofilm components, and signal molecules of the tumor microenvironment required for proliferation, survival, invasion, and metastasis. This Perspective briefly uncovers the main metabolic processes and key factors involved in lipid metabolism reprogramming, mainly related to lipid uptake, de novo synthesis and storage of fatty acids, oxidation of fatty acids, cholesterol synthesis, and related regulatory factors. From a medicinal chemistry perspective, agents against related key targets are reviewed, expecting to pave the way for promising antitumor drugs with prospects for application through lipid metabolism reprogramming.