Sporadic inclusion-body myositis (sIBM) is the most common acquired muscle disease in Caucasians over the age of 50 years. Pathologically it is marked by inflammatory, degenerative, and mitochondrial changes that interact in a yet-unknown way to cause progressive muscle degeneration and weakness. The cause of the disease is unknown, but it is thought to involve a complex interplay between environmental factors, genetic susceptibility, and aging. The strongest evidence for genetic susceptibility comes from studies of the major histocompatibility complex (MHC), where different combinations of alleles have been associated with sIBM in different ethnic groups. The rare occurrence of familial cases of inclusion-body myositis (fIBM) adds additional evidence for genetic susceptibility. Other candidate genes such as those encoding some of the proteins accumulating in muscle fibers have been investigated, with negative results. The increased understanding of related disorders, the hereditary inclusion-body myopathies (hIBM), may also provide clues to the underlying pathogenesis of sIBM, but to date there is no indication that the genes responsible for these conditions are involved in sIBM. This review summarizes current understanding of the contribution of genetic susceptibility factors to the development of sIBM.