CRISPR/Cas is not only an important gene editing tool, but also an effective molecular diagnostic tool. Presently, based on the CRISPR/Cas, a series of molecular diagnostic sensor systems have been established, which are widely used in nucleic acid and non-nucleic acid detection. There have been series reviews of nucleic acid molecular diagnostic sensor system based on CRISPR/Cas. However, there is no systematic review of CRISPR/Cas-based non-nucleic acid detection system. This paper is to review CRISPR/Cas-based non-nucleic acid molecular sensor diagnosis system of characteristics and principles. CRISPR/Cas system of non-nucleic acid molecular sensor diagnosis system is divided into two type, CRISPR/Cas12 and CRISPR/Cas13. Based on CRISPR/Cas12a, detection system of exosomes, CaT-SMelor small-molecule compounds, cell-free biosensors, fDNA-based small-molecule compounds, melamine and ochratoxin was established. Another large class of non-nucleic acid molecular diagnostic sensor systems that based on CRISPR/Cas13 is alkaline phosphatase (ALP) activity and pathogen detection system. The advantages of CRISPR/Cas of molecular diagnosis in vitro have been demonstrated. Therefore, the basic work flow, detection principle and characteristics of non-nucleic acid molecular diagnosis based on CRISPR/Cas molecular diagnosis sensor system are reviewed in this paper. It is expected to provide a basis for the application of CRISPR/Cas-based molecular diagnostic system in in vitro diagnosis.