Inflammation and immune dysfunction occur with inhalation exposure to fibrous (asbestiform) silicon oxide dusts. As research delves deeper, it is clear that despite some commonalities in the responses to mineral fibers, there appear to be distinct differences in the specific nature of the dysfunction elicited by various fibers that leads ultimately to fiber-specific disease outcomes. A growing body of evidence supports an association between asbestos exposure and autoimmune responses such as antinuclear antibodies (ANA). However, there is limited epidemiological support for an association between asbestos exposure and any specific autoimmune disease. While there are several possible reasons for this, recent data strongly suggests that a key factor lies in the physical chemistry of the fibers themselves, requiring comparative studies of different fiber types. In order to illustrate the importance of this premise, this chapter explores the current data comparing the autoantibody responses following amphibole exposure with those seen following chrysotile exposure. Both human and mouse data suggest that amphibole, but not chrysotile, increases the frequency of positive ANA tests and may increase the risk for systemic autoimmune diseases such as systemic lupus erythematosus. Asbestiform amphibole also drives production of pathogenic autoantibodies against mesothelial cells that appear to contribute to a severe and progressive pleural fibrosis. While occupational asbestos exposures may be decreasing, environmental exposures are on the rise as evidenced by multiple recent discoveries of naturally occurring asbestos. These findings emphasize the need for renewed efforts toward screening and understanding fiber-specific disease manifestations.