Colorectal cancer (CRC) is a heterogeneous disease with various genetic and epigenetic factors leading to difficulties in response to both the therapy and drug resistance. Moreover, even in tumors with similar histopathological characteristics, different responses and molecular features could be observed because of the genetic basis and its interactions with the living environment. Through personalized medicine, we can classify patients into separate groups according to their genetic and epigenetic features and their susceptibility for a specific disease which could help with choosing the best therapeutic approach. In this review, genetic and epigenetic factors that cause heterogeneity in colorectal cancer are evaluated and proper drug administration in both chemotherapy and target therapy are suggested.