Alpha-1 antitrypsin deficiency is predominantly caused by point mutations that alter the protein’s folding. These mutations fall into two broad categories: those that destabilize the protein dramatically and lead to its post-translational degradation and those that affect protein structure more subtly to promote protein polymerization within the endoplasmic reticulum (ER). This distinction is important because it determines the cell’s response to each mutant. The severely misfolded mutants trigger an unfolded protein response (UPR) that promotes improved protein folding but can kill the cell in the chronic setting. In contrast, mutations that permit polymer formation fail to activate the UPR but instead promote a nuclear factor-κB–mediated ER overload response. The ability of polymers to increase a cell’s sensitivity to ER stress likely explains apparent inconsistencies in the alpha-1 antitrypsin–signaling literature that have linked polymers with the UPR. In this review we discuss the use of mutant serpins to dissect each signaling pathway.