Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health. This is compounded by the limited efficacy of available treatments and high failure rates during drug development – highlighting an urgent need to better understand disease mechanisms. I will discuss our recent work that shows how functional genomics can address this challenge. By investigating an intergenic haplotype on chr21q22, independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis, we discover a central regulator of inflammatory responses in human macrophages and delineate a shared disease mechanism that can be targeted therapeutically.