Physiological strategic crossing in wheat uses conceptual models, diverse genetic resources and molecular genetic variability in order to design improved germplasm. Crosses designed under this approach make use of complementary traits to achieve cumulative gene action for higher yield (e. g. source and sink traits). Testing this genetic advantage will be crucial to proof the strategic crossing concept. Thus, the present study aimed to evaluate the performance of the nursery Wheat Yield Collaboration Yield Trial (WYCYT) (developed at CIMMYT) under Mexican irrigated environments. This nursery was targeted for high yield potential irrigated environments across the globe. Crosses were designed with one parent selected for favorable source (e. g. biomass) and sink (e. g. harvest index) traits. Performance of this nursery under Mexican growing irrigated environments was evaluated by establishing the 2th and 3th WYCYT's in locations at Baja California, Sonora, Sinaloa, Jalisco and Guanajuato and 4th and 5th WYCYT's in the same locations but adding one more location at Coahuila. Genetic advantage of wheat lines derived from physiological strategic crossing showed significant superior grain yield than local checks in the 3th, 4th and 5th WYCYT's (26.1, 12.9 and 11.2, respectively). Interestingly, 5th WYCYT also showed higher grain yield than a CIMMYT check Borlaug 100 (best current elite line developed under conventional breeding). Our results also indicated that biomass and harvest index were strongly correlated with grain yield in all four nurseries (Pearson correlation coefficients ranging from 0.66 to 0.74). Moreover, best high yielding physiological strategic crosses were top ranked for biomass expression and showed harvest index values in the range of 0.40 and 0.48. These results indicated that designing crosses with parental lines with high expression of biomass (source trait) and good expression of sink traits (e. g. harvest index) can give genetic advantages and increase grain yield.