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Liver X receptors (LXR) are members of the nuclear receptor family. As activated transcription factors, their putative association with human diseases makes them promising pharmacological targets because of the large potential to develop ligands. LXR are mainly considered as intracellular cholesterol “sensors” whose activation leads to decreased plasma cholesterol. They also modulate numerous physiological functions: fatty acid synthesis and metabolism, glucose homeostasis, steroidogenesis, immunity, and neurological homeostasis. LXR-deficiency in mouse results in several phenotypes mimicking pathological conditions in humans. This review will be focused on the various natural and synthetic LXR agonists and antagonists. Putative clinical targets including atherosclerosis, diabetes, Alzheimer’s disease, skin disorders, and cancer will be covered.