In this review, the authors focus on clinical aspects of central nervous system (CNS) atrophy in multiple sclerosis (MS), including the relationship between atrophy and disability, disease course, disease duration, quality of life, and fatigue. Cross-sectional studies have demonstrated a moderate but significant correlation between brain or spinal cord atrophy and physical disability in patients with MS. Longitudinal studies (>/= 5 years) have shown that CNS atrophy is a significant predictor of subsequent long-term neurologic deterioration. The clinical relevance of CNS atrophy is reinforced by studies showing that atrophy accounts for more variance than conventional lesion measures in predicting disability. Impaired quality of life and both urodynamic and sexual dysfunction, but not fatigue, are associated with brain atrophy. It is likely that once the level of CNS atrophy reaches a critical threshold, patients begin to suffer clinical impairment and disease progression. Longitudinal studies suggest that CNS atrophy may occur in patients with clinically isolated demyelinating syndromes who are at high risk for developing clinically definite MS. Longitudinal natural history studies in relapsing-remitting, secondary progressive, and primary progressive MS have suggested that patients develop CNS atrophy at a faster rate in the first few years of disease than later in the disease course. Similarly, long-term follow-up studies have shown a poor relationship between disease duration and the rate of brain atrophy. The authors conclude that measurement of atrophy of the CNS is emerging as a clinically relevant biomarker of the MS disease process.