Osteopontin (Opn) is a multifunctional protein independently discovered by investigators from diverse scientific backgrounds and implicated in a broad array of pathological processes. Opn exists both intra- and extracellularly and in numerous pre- and post-translational isoforms. Structurally Opn resembles a matrix protein yet it has well-characterized cytokine like properties including the regulation of cellular migration and cell-mediated immunity. It has thus been classified as both a matricellular protein and a cytokine. Opn is among the most abundantly expressed proteins in a range of lung diseases and has been shown to regulate aspects of pulmonary granuloma formation, fibrosis, and malignancy. Future studies will explore the diagnostic and therapeutic potential of modulating the function of Opn in vivo.