Background: The pathophysiology of idiopathic frozen shoulder (FS) remains poorly described. There is a lack of differentiation between idiopathic and secondary cause. The aim of this systematic review was to summarize the evidence regarding the pathophysiology of idiopathic FS on a molecular level and emphasize the clinical relevance. Methods: A database search of Medline, EMBASE and Cochrane Central Register of Controlled Trials from inception to April 2018 was performed. Participants who underwent previous injections or surgeries were excluded. A thorough selection and quality assessment process using the Cochrane Risk of Bias assessment tool and the Joanna Briggs Institute Critical Appraisal Checklist was conducted by two reviewers independently. Results: A total of 15 studies analyzing 333 study subjects were included. Twelve studies evaluated capsular tissue and three studies investigated blood samples. The tissue samples revealed increased expression of various inflammatory cytokines including interleukins, cyclooxygenase and tumor necrosis factor. Several types of acid-sensing ion channels (ASIC1 and ASIC3) were associated with disturbed neurogenesis and melatonin-regulated pain mechanism. The blood samples showed prevalence of specific interleukin and metalloproteinase genotypes. A decreased matrix metalloproteinase/tissue inhibitor of metalloproteinase ratio was found both in tissue and blood. Conclusion: The findings indicate an abnormal local neurogenesis with possible regulation through melatonin. The disturbance in remodeling of the extracellular matrix and in collagen translation, together with a persistent inflammation and an impaired healing, all interact in the process that leads to persistent fibrosis. There is global fibroplasia with localized anterior capsule contracture.