<p>This review critically evaluates recent advances in understanding the adverse effects of thermal pollution on rainbow trout (<i>Oncorhynchus mykiss</i>), focusing on the integrated roles of heat shock proteins (HSPs) and acute-phase proteins (APPs) in stress adaptation. The primary objective is to clarify mechanistic pathways through which temperature elevation and fluctuations, often driven by anthropogenic activities, disrupt homeostasis and trigger molecular and systemic stress responses in this cold-water species. The review synthesizes experimental and field findings to outline how distinct thermal stressors influence the expression, induction and functional modulation of HSPs and APPs, which act as biomarkers and mediators of resilience through protein folding, oxidative balance, immune signaling and survival mechanisms. Major topics include: (i) characterization of HSP families (e.g., HSP70, HSP90) in thermal responses; (ii) APP-mediated inflammation and immune modulation and (iii) molecular networks linking heat shock signaling to physiological outcomes such as altered growth and reproduction. Although considerable progress has been made, variability across study conditions restricts generalization. Future research should focus on (i) defining the specific functional roles and cross-talk of small HSPs (sHSPs) under chronic stress, (ii) investigating epigenetic mechanisms underlying intergenerational thermotolerance and (iii) applying integrated multi-omics approaches to map regulatory interactions between HSPs, APPs and overall stress physiology under climate-driven warming. These efforts will guide strategies to strengthen thermal resilience and welfare in aquaculture and conservation.</p>