ABCC4 is an ATP-dependent transporter of the ABC family that actively extrudes physiological compounds and xenobiotics from cells. The transporter handles a diverse substrate repertoire including cyclic nucleotides (cAMP and cGMP), bile acids, urate, prostaglandins, and glutathione conjugates such as leukotriene C4 and leukotriene B4. ABCC4 also transports a wide range of anticancer, antiviral, and antibiotic drugs and their metabolites, conferring resistance to agents including methotrexate 1. In airway epithelial cells, ABCC4 physically couples with CFTR in membrane microdomains to orchestrate cAMP-dependent signaling and substrate transport in both health and disease 2. Recent structural studies reveal that ABCC4 exhibits binding flexibility across substrates; cAMP transport is stabilized through protein kinase A-induced assembly of a PDZ-dependent macromolecular complex that anchors ABCC4 to actin and junction proteins 3. ABCC4 also transports platelet agonists and antagonists, positioning it as a potential target for cardiovascular disease prevention 4. Clinical relevance includes associations with methotrexate toxicity in pediatric acute lymphoblastic leukemia, where ABCC4 variants modulate rescue drug requirements 1, and with multidrug resistance in gastric and prostate cancers, where ABCC4 inhibition or silencing restores chemosensitivity 56.