As sessile organisms, plants are subjected to variety of stresses for which they have evolved different protection mechanisms. One mechanism involves endoplasmic reticulum (ER) stress in which the process of protein folding is disturbed and misfolded proteins accumulate in the ER. ER stress elicits the unfolded protein response (UPR) whereby the stress conditions in the ER are communicated to the nucleus to regulate stress response genes. Since the UPR is one of a number of different mechanisms by which plants respond to stress, it is often difficult to distinguish the UPR from other stress responses. Many investigators have relied on the molecular signature of the UPR, the upregulation of UPR genes to implicate the UPR in response to various stresses. However, some of these genes are activated by other stresses making it problematic to know whether the UPR is truly activated in response to a given stress or is part of a complex response. Another challenge is to understand how plants actually perceive different stress conditions. Are all stress conditions that elicit the UPR response caused by an accumulation of misfolded proteins in the ER? Is this the case for salt stress, which induces the UPR? How about biotic stresses, such as bacterial or viral infections? Do they lead to the accumulation of misfolded proteins in the ER or are there other means by which they induce the UPR?