Cardiometabolic diseases profoundly remodel tissue immune landscapes, characterized by the accumulation of diverse macrophage subtypes. Among these, lipid-associated macrophages (LAMs) have emerged as an important subset that is frequently observed in cardiometabolically affected tissues. LAMs are defined by a transcriptional profile linked to lipid metabolism and processing. In parallel, the nuclear receptor liver X receptor (LXR), is a key transcription factor that regulates cholesterol efflux, fatty-acid synthesis, as well as inflammation pathways. Through these pathways, LXR agonism has been shown to limit atherosclerosis progression but also to promote hepatic steatosis. Beyond lipid metabolism, LXRs exert important immunoregulatory functions. In murine macrophages, LXR activation consistently dampens inflammatory responses. In contrast, human macrophages show more heterogeneous responses, with several studies indicating that LXRs can also promote pro-inflammatory gene programs. These species-specific differences highlight a critical gap that currently limits the translation of preclinical findings. In this review, we integrate recent insights of LXRs in LAMs and cardiometabolic disease, emphasizing species-specific differences in macrophage LXR signaling between mice and humans. We discuss the contribution of LXR isoforms and emerging mechanisms by which LXRs influence inflammatory responses, and consider their implications for therapeutic targeting.