A firmer understanding of the genomic landscape of lung cancer has recently led to targeted, therapeutic advances in non‐small cell lung cancer. Historically, the reference standard for the diagnosis and genetic interrogation for advanced‐stage patients has been tissue acquisition via computed tomography‐guided core or fine needle aspiration biopsy. However, this process can frequently put the patient at risk and remains complicated by sample availability and tumor heterogeneity. In addition, the time required to complete the diagnostic assays can negatively affect clinical care. Technological advances in recent years have led to the development of blood‐based diagnostics or “liquid biopsies” with great potential to quickly diagnose and genotype lung cancer using a minimally invasive technique. Recent studies have suggested that molecular alterations identified in cell‐free DNA (cfDNA) or circulating tumor DNA can serve as an accurate molecular proxy of tumor biology and reliably predict the response to tyrosine kinase therapy. In addition, several trials have demonstrated the high accuracy of microRNA (miRNA) platforms in discerning cancerous versus benign nodules in high‐risk, screened patients. Despite the promise of these platforms, issues remain, including varying sensitivities and specificities between competing platforms and a lack of standardization of techniques and downstream processing. In the present report, the clinical applications of liquid biopsy technologies, including circulating tumor cells, proteomics, miRNA, and cfDNA for NSCLC, are reviewed and insight is provided into the diagnostic and therapeutic implications and challenges of these platforms. Implications for Practice: Although tumor biopsies remain the reference standard for the diagnosis and genotyping of non‐small cell lung cancer, they remain fraught with logistical complexities that can delay treatment decisions and affect clinical care. Liquid diagnostic platforms, including cell‐free DNA, proteomic signatures, RNA (mRNA and microRNA), and circulating tumor cells, have the potential to overcome many of these barriers, including rapid and accurate identification of de novo and resistant genetic alterations, real‐time monitoring of treatment responses, prognosis of outcomes, and identification of minimal residual disease. The present report provides insights into new liquid diagnostic platforms in non‐small cell lung cancer and discusses the promise and challenges of their current and future clinical use. 摘要 对肺癌基因组图谱的深入理解使非小细胞肺癌 (NSCLC) 的靶向治疗在近年得到了长足进展。从历史上来说, 肺癌晚期患者的诊断及基因鉴定参考标准物通常为在计算机体层摄影 (CT) 引导下粗针/细针穿刺活检获取的组织。然而, 这一步骤常使患者处于危险之中, 且结果也可能因样本可用性及肿瘤异质性的差异而较为混杂。此外, 完成这一诊断检验需要一定的时间, 这可能对临床治疗造成不利的影响。近年来临床技术的进展引领了基于血液的诊断学 (或称“液体活检”) 的飞速发展, 从而使应用微创技术对肺癌进行快速诊断和基因分型成为可能。最近有研究提示从无细胞DNA (cfDNA) 或循环肿瘤细胞中发现的分子学突变可以作为肿瘤活检的一项精准分子指标, 进而能可靠地预测患者对酪氨酸激酶抑制剂 (TKI) 治疗的反应。另外, 多项研究均证实microRNA (miRNA) 平台在高危筛查患者中鉴别恶性与良性结节时具有高准确性。尽管这些平台的前景令人瞩目, 但目前尚有许多问题, 包括各竞争平台之间敏感性和特异性的差异, 以及技术和下游操作程序缺乏规范化标准等。本文回顾总结了液体活检技术在NSCLC中的临床应用, 包括循环肿瘤细胞、蛋白质组学、miRNA及cfDNA等, 并对这些平台在诊断和治疗上的临床意义及面临的挑战提出了展望。The Oncologist 2016;21:1121–1130 对临床实践的提示: 尽管肿瘤活检是非小细胞肺癌诊断和基因分型的参考标准, 但其流程复杂, 可能延误治疗决策并影响临床治疗。液体诊断平台 包括无细胞 DNA、蛋白质组学信号、RNA (mRNA 和 miRNA) 及循环肿瘤细胞 有潜力克服这些障碍, 如快速并准确鉴定新发及耐药基因突变、实时监测治疗应答、预测患者转归并发现微小残留病灶等。本文对非小细胞肺癌的新型液体诊断平台提出了展望, 并讨论了当前和将来临床应用的前景和挑战。 Technological advances in recent years have led to the development of blood‐based diagnostics or “liquid biopsies” with great potential to quickly diagnose and genotype lung cancer using a minimally invasive technique. The clinical applications of liquid biopsy technologies, including circulating tumor cells, proteomics, microRNA, and cell free DNA for lung cancer, are reviewed and insight is provided into the diagnostic and therapeutic implications and challenges of these platforms.