Idiopathic pulmonary fibrosis (IPF) remains a relentlessly progressive lung disorder despite four decades of interest in its pathogenesis and treatment. It is important to emphasize that IPF is a progressive and irreversible illness, and, until now, there has been no available drug that has been capable of modifying the progressive natural course of IPF and its usual terminal outcome. Although the pathogenesis of this disease is complex and poorly understood, growth factors, cytokines, chemokines, and regulators of apoptosis have all been implicated in its pathogenesis and disease progression. This review summarizes the evidence implicating these molecules as primarily involved in the pathogenesis of IPF such as cytokines, chemokines and growth factors, with particular emphasis to novel interactions. The elucidation of mediators that orchestrate this aberrant tissue repair will allow the development of novel interventions to treat this devastating disorder.