The NR4A1-NR4A3 (Nur77, Nurr1, and Nor-1) subfamily of nuclear receptors is a group of immediate early genes induced by a pleiotropy of stimuli including peptide hormones, growth factors, cytokines, inflammatory, and physiological stimuli, and cellular stress. NR4A receptors function as potent sensors of changes in the cellular microenvironment to control physiological and pathological processes through genomic and non-genomic actions. NR4A receptors control metabolism and cardiovascular and neurological functions and mediate immune cell homeostasis in inflammation and cancer. This receptor subfamily is increasingly recognized as an important molecular connection between chronic inflammation, altered immune cell responses, and cancer development. In this review, we examine how transcriptome analysis identified NR4A1/NR4A2 receptors as transcriptional regulators in mesenchymal stromal cell (MSC) migration, cell cycle progression, and cytokine production to control local immune responses. In chronic inflammatory conditions, such as rheumatoid arthritis, NR4A receptors have been shown to modify the activity of MSC and fibroblast-like stromal cells to regulate synovial tissue hyperplasia, pathological angiogenesis, and cartilage turnover . Additionally, as NR4A1 has been observed as a major transcriptional regulator in tumor-stromal communication controlling tumorigenesis, we discuss how advances in the pharmacological control of these receptors lead to important new mechanistic insights into understanding the role of the tumor microenvironment in health and disease.