Malignant pleural effusions (MPEs) are a common and important cause of cancer-related mortality and morbidity. Prompt diagnosis using minimally invasive tests is important because the median survival after diagnosis is only 4-9 months. Pleural fluid cytology is pivotal to current MPE diagnostic algorithms but has limited sensitivity (30-60%). Consequently, many patients need to undergo invasive diagnostic tests such as thoracoscopic pleural biopsy. Recent genomic, transcriptomic, methylation and proteomic studies on cells within pleural effusions have identified novel molecular diagnostic biomarkers that demonstrate potential in complementing cytology in the diagnosis of MPEs. Several challenges will need to be addressed prior to the incorporation of these molecular tests into routine clinical diagnosis, including validation of molecular diagnostic markers in well-designed prospective, comparative and cost-effectiveness studies. Ultimately, minimally invasive diagnostic tests that can be performed quickly will enable clinicians to provide the most effective therapies for patients with MPEs in a timely fashion.