In this work, appropriate management practices for crop production under the variable climate conditions of the Mediterranean region, in particular rainfall, were tested with the use of a modelling system applied to long-term (i.e. 18 years) field data. The calibration of the CropSyst model was performed using data collected from 1996 to 1999 at three different Mediterranean locations (i.e., HYP-Guissona, MYP-Agramunt and LYP-Candasnos, i.e. high, medium and low yield potential, respectively) within a degree of yield potential. The model simulated reasonably well barley growth and yield to different tillage and N fertilization strategies. Simulations of barley performance over 50 years with generated weather data showed that yields were often greater and never smaller under no-tillage compared to conventional tillage with a mean increase of 36%, 63% and 18% for HYP-Guissona, MYP-Agramunt and LYP-Candasnos. In MYP-Agramunt, the long-term data showed a 40% increase in grain yields when using no-tillage compared to conventional tillage, as an average of 18 years. The model also predicted that greater N applications in no-tillage were appropriate to take advantage of additional water supply. Taking into account the limited amount of soil water available, overall N fertilizer applications could be reduced to about half of the traditional rate applied by the farmers without yield loss. The 50-yr simulation, confirmed by the long-term experimental data, identified no-tillage as the most appropriate tillage practice for the rainfed Mediterranean areas. Also, N fertilization must be reduced significantly when tillage is used or when increasing aridity. Our work demonstrates the usefulness of the combination of long-term field experimentation and modelling as a tool to identify the best agricultural management practices. It also highlights the importance of posterior analysis with long-term observed field data to determine the performance of simulation results. This work was funded by the Comisión Interministerial de Ciencia y Tecnología (CICYT) of the Spanish National Plan of Research, projects AGR94-198, AGF98-0261-C02, AGL2001-2238-CO2-02, AGL2004-07763-CO2-01-AG, AGL2007-66320-C02-C02-01/AGR, AGL2010-22050-C03-01 and the Instituto Nacional de Investigaciones Agrarias (INIA), project PD96-029. We also thank the Ministry of Education and Culture, which funded the doctorate studies of P. Angás. Daniel Plaza-Bonilla received a “Juan de la Cierva” grant from the Ministerio de Economía y Competitividad of Spain.