With an approach combining crop modelling and biotechnology to assess the performance of three durum wheat cultivars (Creso, Duilio, Simeto) in a climate change context, weather and agronomic datasets over the period 1973–2004 from two sites, Benatzu and Ussana (Southern Sardinia, Itay), were used and the model responses were interpreted considering the role of DREB genes in the genotype performance with a focus on drought conditions. The CERES-Wheat crop model was calibrated and validated for grain yield, earliness and kernel weight. Forty-eight synthetic scenarios were used: 6 scenarios with increasing maximum air temperature; 6 scenarios with decreasing rainfall; 36 scenarios combining increasing temperature and decreasing rainfall. The simulated effects on yields, anthesis and kernel weights resulted in yield reduction, increasing kernel weight, and shortened growth duration in both sites. Creso (late cultivar) was the most sensitive to simulated climate conditions. Simeto and Duilio (early cultivars) showed lower simulated yield reductions and a larger anticipation of anthesis date. Observed data showed the same responses for the three cultivars in both sites. The CERES-Wheat model proved to be effective in representing reality and can be used in crop breeding programs with a molecular approach aiming at developing molecular markers for the resistance to drought stress.