During the last decade, many approaches have been proposed for improving the estimation of diffusion measures. These techniques have already shown an increase in accuracy based on theoretical considerations, such as incorporating prior knowledge of the data distribution. The increased accuracy of diffusion metric estimators is typically observed in well-defined simulations, where the assumptions regarding properties of the data distribution are known to be valid. In practice, however, correcting for subject motion and geometric eddy current deformations alters the data distribution tremendously such that it can no longer be expressed in a closed form. The image processing steps that precede the model fitting will render several assumptions on the data distribution invalid, potentially nullifying the benefit of applying more advanced diffusion estimators. In this work, we present a generic diffusion model fitting framework that considers some statistics of diffusion MRI data. A central role in the framework is played by the conditional least squares estimator. We demonstrate that the accuracy of that particular estimator can generally be preserved, regardless the applied preprocessing steps, if the noise parameter is known a priori. To fulfill that condition, we also propose an approach for the estimation of spatially varying noise levels. Magn Reson Med, 70:972–984, 2013. © 2012 Wiley Periodicals, Inc.