Lipid metabolism has been increasingly recognized to play an influencing role in tumor initiation, progression, metastasis, and therapeutic drug resistance. Targeting lipid metabolic reprogramming represents a promising therapeutic strategy. Despite their structural complexity and poor targeting efficacy, lipid-metabolizing drugs, either used alone or in combination with chemotherapeutic agents, have been employed in clinical practice. The advent of nanotechnology offers new approaches to enhancing therapeutic effects, includingthe targeted delivery and integration of lipid metabolic reprogramming with chemotherapy, photodynamic therapy (PDT), and immunotherapy. The integrated nanoformulation, nanomedicine, could significantly advance the field of lipid metabolism therapy. In this review, we will briefly introduce the concept of cancer lipid metabolism reprogramming, then elaborate the latest advances in engineered nanomedicine for targeting lipid metabolism during cancer treatment, and finally provide our insights into future perspectives of nanomedicine for interference with lipid metabolism in the tumor microenvironment.