Although identified over a decade ago, the function and physiological significance of the mammalian Schnurri protein family remained largely unknown. However, the recent generation and characterization of mice bearing null mutations in the individual Schnurri genes has led to the discovery of unexpected yet central roles for these large zinc-finger proteins in several biological processes. Here, we review findings of these studies and discuss the importance of the Schnurri protein family in regulating both the immune and skeletal systems.