Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown cause, characterised by progressive worsening in lung function and dyspnoea with an associated prognosis similar to or worse than many cancers. As a better understanding emerges around the pathogenesis and mechanisms driving disease pathology, a host of novel agents are being tested both pre-clinically and clinically. However even with this deeper understanding and positive pre-clinical supportive data, negative trial outcomes are frequently reported, highlighting the problems faced in treating such a heterogeneous disease with a varied clinical course. Recently, two therapies that slow disease progression, nintedanib and pirfenidone, have been approved for the treatment of IPF, yet the clinical unmet need is still high for IPF patients given their failure to stop disease progression and their potential side-effect profiles. Efforts are being made to not only understand the underlying pathways and genetics that might influence the clinical course of the disease, but also the non-invasive biomarkers that reflect the activity of specific pathways which in turn may highlight progressive treatment plans for individual patients. The cumulative data may be based on the identification of subgroups of patients via biomarker analysis of ongoing clinical trials, or investigation of cohorts of patients over time to understand the relative role of these mediators in their disease progression. Below we review the ongoing quest for novel therapeutic approaches and highlight, where appropriate attempts have been made to identify patients for which a specific pathway or mediator may be driving disease progression. (C) 2016 Elsevier Inc. All rights reserved.