The first gene therapy product, recombinant adenovirus human p53 (rAd-p53), has been approved by CFDA since 2013. During these years, most of the clinical trials and the relevant basic research were carried out by Chinese oncologists. Gendicine was proved to be a safe and promising gene therapy drug for patients who suffered from head and neck squamous cell carcinoma (HNSCC). The basic therapeutic theories of gene therapy were totally different from the traditional ones, such as surgeries or radio- and chemotherapy, and the evaluation of treatment outcomes should also be changed simultaneously. However, there still existed a lot of misunderstandings about gene therapy, which resulted in improper administration, insufficient dosage calculation, and treatment cycles, and the treatment outcomes were unsatisfactory, especially for inexperienced oncologists or hospitals. Therefore, we will provide some practical guidance here on the gene therapy of rAd-p53 based on our previous research and experience, which focused on the basic theories and clinical issues, to answer the questions arising during the clinical of gene therapy and to accelerate the development of gene therapy for the benefit of patients bearing malignant tumors.