Lipotoxicity is a common pathological process underlying obesity, insulin resistance, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiometabolic abnormalities. Rather than simply reflecting an increase in total lipid content, lipotoxicity arises from a mismatch among lipid uptake, storage, mobilization, oxidation, and organelle quality control, which shifts fatty acids away from safe storage and efficient utilization toward the sustained accumulation of toxic lipid intermediates. Current evidence therefore suggests that the protective effects of exercise against lipotoxicity should be understood as a systematic remodeling of lipid fate rather than merely as a reduction in fat deposition. Exercise can promote the channeling of fatty acids into relatively safe triacylglycerol stores and dynamic lipid droplet pools, while improving lipid droplet size, subcellular localization, perilipin (PLIN) protein decoration, and lipid droplet turnover. At the same time, exercise enhances lipid droplet–mitochondria functional coupling, mitochondrial fatty acid oxidation, respiratory capacity, and metabolic flexibility, thereby increasing the probability that mobilized fatty acids are efficiently oxidized instead of being diverted toward diacylglycerols, ceramides, acylcarnitines, and oxidized lipids. Exercise also modulates endoplasmic reticulum stress, oxidative stress, inflammatory signaling, autophagy/lipophagy, mitophagy, and inter-organ communication, linking lipid handling to broader organelle homeostasis and tissue protection. These adaptations are tissue specific. In skeletal muscle, exercise-induced changes in intramyocellular lipid content should be interpreted together with lipid droplet quality, subcellular distribution, PLIN-associated remodeling, and mitochondrial oxidative capacity, which helps explain the athlete""s paradox. In the liver, exercise affects lipid input, lipid droplet clearance, lipophagy, mitochondrial oxidation, and stress-response pathways, providing a mechanistic basis for its beneficial effects in MASLD and related metabolic disorders. In the heart, the protective effects of exercise depend more strongly on the balance between fatty acid uptake, lipid mobilization, and mitochondrial oxidative capacity, and excessive lipid redistribution under certain metabolic conditions may increase cardiac lipotoxic stress. Adipose tissue further contributes by regulating free fatty acid overflow and systemic lipid supply, while muscle-, liver-, adipose-, vascular-, and gut-derived signals participate in cross-organ metabolic coordination. Importantly, the evidence base is heterogeneous: human studies mainly support changes in lipid droplet phenotype, insulin sensitivity, metabolic flexibility, and tissue function, whereas animal and cellular studies provide stronger mechanistic evidence for specific molecular pathways and organelle interactions. Therefore, mechanistic findings from experimental models should not be directly equated with human exercise responses. This review integrates current evidence from skeletal muscle, liver, heart, and adipose tissue and proposes "lipid fate remodeling" as a unifying framework for exercise-mediated protection against lipotoxicity. Future studies should move beyond static measurements of total lipid content and incorporate lipid molecular species, subcellular localization, lipid flux, organelle interactions, mitochondrial function, and individualized exercise prescription. Such an approach may improve mechanistic interpretation and help identify when exercise promotes adaptive lipid handling and when exercise-induced lipid mobilization may exceed tissue oxidative capacity. Accordingly, the translational goal of exercise prescription should be to restore the dynamic matching among lipid input, lipid droplet buffering, controlled lipolysis, mitochondrial oxidation, and organelle quality control, rather than to maximize lipid mobilization or fat oxidation in isolation.