Mammalian cells entrust virtually all communication of extracellular signals to a remarkably small number of signaling systems. Moreover, many of these share components raising the question of how signal specificity is achieved. One of the most polygamous of these of these is a protein kinase, glycogen synthase kinase-3 (GSK-3), that acts to negatively regulate at least 7 distinct pathways. Using tissue-selective knockout mouse models in liver, mammary gland and lymphocytes, I will describe the layers of regulation that confer signal authenticity and insulation and discuss implications for experimental and therapeutic interventions that fail to discriminate between compartments of target molecules. The liver and lymphocyte results also shed new light on the importance of zonation and elimination of non-functional T cells.