Changes of lesion load on yearly conventional spin echo (CSE) T2-weighted scans of the brain from patients with multiple sclerosis, measured using computer assisted techniques, are used to monitor long term disease evolution, either natural or modified by treatment. Although lesion load measurements have several advantages over clinical measures of outcome (they provide a more objective and sensitive measure of disease evolution, which has a linear distribution and a more strict relation with the underlying pathology), the poor correlation between changes of lesion load and changes of disability is of concern when using such an approach for monitoring multiple sclerosis trials. In this review, the main sources of variation in T2 lesion load from brain MRI of patients with multiple sclerosis will be considered, along with possible strategies to, at least partially, overcome them. Also, some of the newer fully automated techniques to segment multiple sclerosis lesions, which have been validated against manual outlining, and a recently developed coregistration technique are presented. It is hoped that a more reliable and standardised approach to lesion load measurements in multiple sclerosis will lead to better correlation with clinical disease course, to a higher confidence in the results of trials, and to reduced numbers of scans needed to conduct the trials, thus improving cost efficiency and reducing discomfort of the patients.