Precision medicine based on big data is an attractive research field in colorectal cancer. Though the next generation sequencing (NGS) technology has developed rapidly, the challenges from science and practice aspects make the clinical progress fairly slow. In addition to EGFR, MLH1, PIK3CA and KRAS gene abnormalities, no other specific oncogenic driver mutations are found in colorectal cancer, so the biggest challenge is the identification of driver mutations. The development of bioinformatics tools, the application of deep sequencing and circulating tumor DNA (ctDNA) monitoring are helpful to determine rare driver gene mutation rate, assess pathways activation and combine different treatments, which can solve the above problems in future. The change in most candidate genomes is small, which hampers the clinical practice of precision medicine. Individual basket trial or umbrella trial may conquer the limitation.