It is the primary goal of disease modifying treatments in multiple sclerosis (MS) to prevent the occurrence of new clinical deficits and lessen or prevent accumulation of disability. As a consequence, clinical aspects constitute the major outcome variables in treatment trials and are also the leading factor for treatment decisions in individual patients. However, determining treatment efficacy by clinical evaluation suffers from limited objectivity, sensitivity, and specificity for the underlying pathophysiologic aspects, which may constitute the target of a given therapy. Magnetic resonance imaging (MRI) can partly overcome these limitations by showing morphologic aspects of the disease with clinical relevance and responsiveness to therapy. Within the past 10 years sufficient data have been collected to establish the accumulation of new/enlarging T2 lesions and gadolinium enhancing lesions, T2 lesion load, T1-hypointense lesions, and brain volume changes as reasonably well-defined markers of disease processes, which may serve to monitor treatment efficacy. Accordingly, these variables have been extensively used for probing the efficacy of disease modifying treatments. In part they are also suited to guide therapeutic decisions in the individual patient. Further options may come from the use of advanced techniques like magnetization transfer MRI, diffusion-weighted MRI, and proton magnetic resonance spectroscopy, which detect more subtle MS related tissue abnormalities. Irrespective of the technique employed, great care has to be given to the standardization and reproducibility of both data acquisition and interpretation when using MRI to monitor treatment efficacy. For the individual patient therapeutic decisions based on MRI need experience and caution.