Because they are objective and reproducible, inverse modeling procedures are increasingly used to identify model parameters that cannot be easily measured. This study investigated the feasibility of using inverse methods to estimate parameters describing macropore flow, transport, and transformation processes in the dual-permeability model MACRO. MACRO was linked to the inverse modeling package SUFI, and we used numerically generated data representing transient leaching experiments for tracers and reactive solutes in microlysimeters (21-cm height). Attention was focused on parameter sensitivity, availability of experimental data (flux and resident concentrations), the degree of macropore flow in the system, and the significance of experimental errors. Reliable results were obtained in the case of strong macropore flow, but both resident and flux concentrations were needed. However, the uncertainty in d, the parameter describing mass exchange between microporosity and macroporosity, remained large, and the adsorption coefficient could not be estimated accurately. Response surface analysis showed that this was due to a lack of sensitivity to d and to internal correlation between adsorption and degradation parameters. In the case of equilibrium flow, the model was overparameterized, and the parameters related to macropore flow were not sensitive enough to be estimated properly. Experimental errors did not affect the feasibility of the procedure, although the uncertainty in the estimates increased. SUFI linked to MACRO appears to be a promising tool for optimization of the system parameters in soils affected by macropore flow, but the “experimental” design needs to be improved for reliable determination of the mass exchange parameter and the adsorption coefficient.