Aquaculture of the northern quahogs Mercenaria mercenaria is an important industry in Florida and involves over 350 small family-based farms. Summer heat is a major environmental challenge for the sustainability of the industry. For aquatic organisms, water temperature is a critical factor in controlling growth, metabolic rates, and immune responses. Breeding of quahogs for heat tolerance would be an effective way to overcome this challenge and support industry development. Three current farm stocks from Cedar Key, Florida were challenged with heat shock by increasing water temperature at 1°C per day from 24°C to a final temperature of 35°C based on our pilot experiment. The survivors from the heat shock challenge were used as broodstock to produce F1 offspring generation by mass spawning. The survival and growth of the F1 generation in parallel with their control in aquaculture leases were evaluated at different stages. During six months of field nursery from September to March, no differences were found in growth between heat shock and control lines (P ≥ 0.253, shell metrics and body weight), but the heat-shock line showed significantly higher survival than the control line (82.9% vs. 74.0%, P = 0.017), indicating the potential of the heat shock line. Throughout the initial six-month grow-out period, the monthly water temperatures ranged from 14.0 to 26.4℃ (min 5.8℃ and max 29℃). During a seven-month grow-out period from March to November, no difference was found in survivals between the heat-shock line and the control, but the body sizes/weights in the heat-shock line were significantly higher than the control. After about 20 months of field culture, the F1 offspring (heat shock and control) were harvested and brought back to the laboratory for a second heat shock challenge. Comparison of immune response and survival were evaluated, and the data is in the process of analysis. The survivors of quahogs of heat shock and control lines will be used to produce F2 generations with the aid of genomic selection.