Sporadic inclusion-body myositis, the most common muscle disease of older persons, is of unknown cause, and there is no successful treatment. Interest in sporadic inclusion-body myositis has been enhanced by the recent identification within the sporadic inclusion-body myositis muscle fibers of several abnormally accumulated proteins, which provides novel and important clues to the pathogenesis of sporadic inclusion-body myositis.This article summarizes the most recent findings leading to better understanding of the players in the pathogenetic cascade. It is suggested that lymphocytic inflammatory component is probably secondary, and it may contribute only slightly to muscle fiber damage in sporadic inclusion-body myositis. However, it is proposed that the identified abnormal accumulation, aggregation, and misfolding of proteins, combined with and perhaps provoked by an aging intracellular milieu, more essentially lead to the vacuolar degeneration and atrophy of the muscle fibers that are specific to sporadic inclusion-body myositis. Abnormal accumulations of the amyloid-beta precursor protein and of its proteolytic fragment, amyloid-beta, associated with the aging cellular muscle fiber environment, appear to be key pathogenic events.In conceptualizing a treatment for sporadic inclusion-body myositis, the accumulations of amyloid-beta42 and other unfolded proteins are now phenomena to be reckoned with. One would like to stop intracellular increase of the unfolded/misfolded proteins by reducing their formation and/or increasing their disposal. In addition, the identification of factors that would decrease intra-muscle fiber expressions of beta- and gamma-secretases might lead to decreased production of putatively myotoxic oligomeric amyloid-beta42. Better understanding of the mechanisms and consequences of genes that predispose to sporadic inclusion-body myositis, and of human muscle fiber aging, could also provide new avenues toward the therapy of sporadic inclusion-body myositis. How to therapeutically capitalize on the new findings is now the challenge.