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The Root Zone Water Quality Model (RZWQM2) has been used widely for simulating agricultural management effects on crop production and soil and water quality. Although it is a one-dimensional model, it has many desirable features for the modeling community. This article outlines the principles of calibrating the model component by component with one or more datasets and validating the model with independent datasets. Users should consult the RZWQM2 user manual distributed along with the model and a more detailed protocol on how to calibrate RZWQM2 provided in a book chapter. Two case studies (or examples) are included in this article. One is from an irrigated maize study in Colorado to illustrate the use of field and laboratory measured soil hydraulic properties on simulated soil water and crop production. It also demonstrates the interaction between soil and plant parameters in simulated plant responses to water stresses. The other is from a maize-soybean rotation study in Iowa to show a manual calibration of the model for crop yield, soil water, and N leaching in tile-drained soils. Although the commonly used trial-and-error calibration method works well for experienced users, as shown in the second example, an automated calibration procedure is more objective, as shown in the first example. Furthermore, the incorporation of the Parameter Estimation Software (PEST) into RZWQM2 made the calibration of the model more efficient than a grid (ordered) search of model parameters. In addition, PEST provides sensitivity and uncertainty analyses that should help users in selecting the right parameters to calibrate.