Although first cloning of the human ATP receptor P2Y was successful 25 years ago, the exact downstream signaling pathways of P2Y receptor, which can couple to G and G proteins, have remained unclear. Especially the lack of rodent models as well as the limited availability of antibodies and pharmacological tools have hampered examination of P2Y expression and function. Many meaningful observations related to P2Y have been made in primary immune cells, indicating that P2Y receptors are important regulators of inflammation and cell migration, also by controlling mitochondrial activity. Our recent studies have shown that P2Y is upregulated during macrophage development and activates signaling through IL-1 receptor, which is well known for its ability to direct inflammatory and migratory processes. This review summarizes the results of the first transcriptomic and secretomic analyses of both, ectopic and native P2Y receptors, and discusses how P2Y crosstalk with the IL-1 receptor may govern anti-inflammatory and pro-angiogenic processes in human M2 macrophages.