Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs) are standard treatments for advanced non-small-cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. Nowadays, tumor tissues acquired by surgery or biopsy are the routine materials for EGFR mutation analysis. However, the accessibility of tumor tissues is not always satisfactory in advanced NSCLC. Moreover, a high proportion of NSCLC patients will eventually develop resistance to EGFR-TKIs. Invasive procedures, such as surgery or biopsy, are impractical to be performed repeatedly to assess the evolution of EGFR-TKI resistance. Thus, exploring some convenient and less invasive techniques to monitor EGFR-TKI treatment is urgently needed. Circulating cell-free tumor DNA (ctDNA) has a high degree of specificity to detect EGFR mutations in NSCLC. Besides, ctDNA is capable of monitoring the disease progression during EGFR-TKI treatment. Certain serum microRNAs that correlate with EGFR signaling pathway, such as miR-21 and miR-10b, have been demonstrated to be helpful in evaluating the efficiency of EGFR-TKI therapeutics. A commercialized serum-based proteomic test, named VeriStrat test, has shown an outstanding ability to predict the clinical outcome of NSCLC patients receiving EGFR-TKIs. Analysis of EGFR mutations in circulating tumor cells (CTCs) is feasible, and CTCs represent a promising material to predict EGFR-TKI-treatment efficacy and resistance. These evidences suggested that non-invasive techniques based on serum or plasma samples had a great potential for monitoring EGFR-TKI treatment in NSCLC. In this review, we summarized these non-invasive approaches and considered their possible applications in EGFR-TKI-treatment monitoring.