In common with a range of environmental and biological stresses, heat shock results in the accumulation of misfolded proteins and a collection of downstream consequences for cellular homeostasis and growth. Within this complex array of responses, the sensing of and responses to misfolded proteins in specific subcellular compartments involves specific chaperones, transcriptional regulators, and expression profiles. Using biological (ectopic protein expression and virus infection) and chemical triggers for misfolded protein accumulation, we have profiled the transcriptional features of the response to misfolded protein accumulation in the cytosol (i.e., the cytoplasmic protein response [CPR]) and identified the effects as a subcomponent of the wider effects induced by heat shock. The CPR in Arabidopsis thaliana is associated with the heat shock promoter element and the involvement of specific heat shock factors (HSFs), notably HSFA2, which appears to be regulated by alternative splicing and non-sense-mediated decay. Characterization of Arabidopsis HSFA2 knockout and overexpression lines showed that HSFA2 is one of the regulatory components of the CPR.