The advent of more sophisticated histologic and molecular tools to study multiple sclerosis (MS) pathology has contributed to evolving concepts regarding disease initiation and progression. MS lesions display pathologic heterogeneity. It is uncertain whether these observations reflect heterogeneity of the disease or, alternatively, are stage-dependent with multiple mechanisms occurring over the course of disease. Remyelination is present in MS lesions and may be extensive. Apart from myelin and oligodendrocyte damage, axons are also injured in MS and are considered an important pathologic correlate of disability. In addition to axonal damage that occurs in the acute active MS plaque, a low-grade ongoing axonal injury occurs in the MS plaque, periplaque, and normal-appearing white matter. This begins early, accumulates, and likely contributes to disease progression. MS pathology is not restricted to the focal white matter lesion, but also includes diffuse cortical and white matter damage. The apparent dissociation between early inflammation and subsequent disease progression is a well-recognized feature of MS, termed the "inflammation-neurodegeneration paradox." This chapter will summarize new insights into the development and evolution of both focal and global tissue injury in MS.