Simultaneous acquisition of dual-isotope SPECT data offers a number of advantages over separately acquired data; however, simultaneous acquisition can result in cross-contamination between isotopes. In this work we propose and evaluate two frameworks for iterative model-based compensation of cross-contamination in dual-isotope SPECT. The methods were applied to cardiac imaging with technetium-99m-sestamibi and thallium-201, and they were compared with a subtraction-based compensation method using a cross-talk estimate obtained from an auxiliary energy window. Monte Carlo simulations were performed to carefully study aspects of bias and noise for the methods, and a torso phantom with cardiac insert was used to evaluate the performance of the methods for experimentally acquired data. The cross-talk compensation methods substantially improved lesion contrast and significantly reduced quantitative errors for simultaneously acquired data. Thallium image normalized mean square error (NMSE) was reduced from 0.522 without cross-talk compensation to as low as 0.052 with model-based cross-talk compensation. This is compared with a NMSE of 0.091 for the subtraction-based compensation method. The application of a preliminary model for cross-talk arising from lead fluorescence x-rays and collimator scatter gave promising results, and the future development of a more accurate model for collimator interactions would probably benefit simultaneous Tc/Tl imaging. Model-based compensation methods provide feasible cross-talk compensation in clinically acceptable times, and they may ultimately make simultaneous dual-isotope protocols an effective alternative for many imaging procedures.