Rapidly growing mycobacteria (RGM) are environmental organisms classified under the broader category of nontuberculous mycobacteria. The most common RGM to cause human diseases are Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, and Mycobacterium massiliense. Infections due to the RGM are an emerging health problem in the United States. Chronic pulmonary disease and skin/soft-tissue infections are the two most common disorders due to these organisms. Clinical outcomes in the treatment of M. abscessus infections are generally disappointing. Because less is known about the nature of the immune response to M. abscessus than for tuberculosis, we herein highlight the major clinical features associated with infections due to M. abscessus and other RGM, and review the known host immune response to RGM, drawing from experimental animal and clinical studies. Based on in vitro and in vivo murine models, Toll-like receptor 2, dectin-1, tumor necrosis factor (TNF)-α, IFN-γ, leptin, T cells, and possibly neutrophils are important components in the host defense against RGM infections. However, excessive induction of TNF-α by the R morphotype of M. abscessus may allow it to be more pathogenic than the S morphotype. Clinical observations and/or genetic studies in humans corroborate many of the findings in animals in that those with cell-mediated immunodeficiency, genetic defects in IFN-γ-IL-12 axis, and those individuals on TNF-α blockers are at increased risk for nontuberculous mycobacteria infections, including the RGM. However, much remains to be discovered on why seemingly healthy individuals, particularly slender postmenopausal women with thoracic cage anomalies, appear to be at increased risk.