Regulators of G protein signaling (RGS) proteins are emerging as potentially important drug targets. The mammalian RGS protein family has more than 20 members and they share a common ∼120-residue RGS homology domain or “RGS box.” RGS proteins regulate signaling via G protein-coupled receptors by accelerating GTPase activity at active α subunits of G proteins of the G_q and G_i/o families. Most studies searching for modulators of RGS protein function have been focused on inhibiting the GTPase accelerating protein activity. However, many RGS proteins contain additional domains that serve other functions, such as interactions with proteins or subcellular targeting. Here, we discuss a rationale for therapeutic targeting of RGS proteins by regulation of expression or allosteric modulation to permit either increases or decreases in RGS function. Several RGS proteins have reduced expression or function in pathophysiological states, so strategies to increase RGS function would be useful. Because several RGS proteins are rapidly degraded by the N-end rule pathway, finding ways to stabilize them may prove to be an effective way to enhance RGS protein function.