Research on the thermal biology of Antarctic marine organisms has increased awareness of their vulnerability to climate change, as a flipside of their adaptation to life in the permanent cold and their limited capacity to acclimate to variable temperatures. Here, we employed a species-specific microarray of the Antarctic eelpout, Pachycara brachycephalum, to identify long-term shifts in gene expression after 2 months of acclimation to six temperatures between -1 and 9 °C. Changes in cellular processes comprised signalling, post-translational modification, cytoskeleton remodelling, metabolic shifts and alterations in the transcription as well as translation machinery. The magnitude of transcriptomic responses paralleled the change in whole animal performance. Optimal growth at 3 °C occurred at a minimum in gene expression changes indicative of a balanced steady state. The up-regulation of ribosomal transcripts at 5 °C and above was accompanied by the transcriptomic activation of differential protein degradation pathways, from proteasome-based degradation in the cold towards lysosomal protein degradation in the warmth. From 7 °C upwards, increasing transcript levels representing heat-shock proteins and an acute inflammatory response indicate cellular stress. Such patterns may contribute to a warm-induced energy deficit and a strong weight loss at temperatures above 6 °C. Together, cold or warm acclimation led to specific cellular rearrangements and the progressive development of functional imbalances beyond the optimum temperature. The observed temperature-specific expression profiles reveal the molecular basis of thermal plasticity and refine present understanding of the shape and positioning of the thermal performance curve of ectotherms on the temperature scale.