Precision medicine aims to take into account individual variability in all aspects including the baseline condition of the whole body, tumor biology, and treatment responses of both tumor and normal organs for each person in order to form the most effective treatment for the best outcome. This is in contrast to the traditional “one-size-fits-all” or “standard” uniform approach, in which treatments are given based on the overall tolerance in the whole patient population, which cures only a small proportion of patients. For lung cancer, the current precision medicine is largely based on targeted systemic therapy, mostly guided by molecular testing of tumor biopsy, which is normally a small sample of tumor, and often limited by the spatial and temporal heterogeneity of the tumor. Tumor tissue biopsy represents “an issue” in that it can be difficult to obtain and may carry sampling errors. This journal issue of Translational Lung Cancer Research will focus on the role of imaging and blood-based biomarkers for precision medicine, which may provide a unique angle of guidance on top of the knowledge provided by tissue biopsy for a more holistic view on the patient and lung cancer, aiming to achieve a new level of precision medicine.