Major advances have been made in recent years toward the identification of transcription factors that control cell-type-specific gene expression in the skeletal and adaptive immune systems. However, the identification of factors necessary and sufficient to drive production of effector cell proteins such as matrix components and cytokines represents the first step toward understanding how cells in bone and the adaptive system achieve their highly specialized functions. Here, we provide selected examples of counter-regulatory mechanisms that serve to turn down cells involved in extracellular matrix biosynthesis and adaptive immunity at the level of the transcription factors Runx2 and nuclear factor for the activation of T cells.