It is well known that Traditional Chinese Medicine (TCM) has two outstanding academic characteristics: the holistic concept comes from Huang Di Nei Jing, and the syndrome differentiation and treatment comes from Shang Han Lun. These two characteristics denote the two major academic systems of TCM: one is the medical system of Huang Di Nei Jing, also named syndrome differentiation and treatment system of Zang-Fu organs and meridians, focuses on theoretical exploration, which highlights functional connection and emphasizes philosophical thinking. The treatment in this system is based on physiological functions by taking Zang-Fu organs as the main body, Qi, blood, essence, and body fluid as the auxiliary body, and the meridians and collaterals as the connection channels. The other is the syndrome differentiation and treatment system of the six meridians, which emphasizes clinical practice. It encompasses the idea that the six meridians govern various diseases, emphasizes the disease sites and divisional treatment, and pays attention to the precision and appropriateness of prescription-syndrome differentiation. These two academic systems, with mutual influences and relations, are both the essence and pearl of TCM, nevertheless, there are obvious differences between the two in clinical application, so they should be distinguished. This paper will elaborate on the connection and difference between them, and how to organically combine the two systems for better application in clinical practice of TCM.