Over the last years, molecular studies through high-throughput technologies have led to the confirmation of critical alterations in colorectal cancer (CRC) and the discovery of some new ones, ranging from mutations, DNA-methylations and structural chromosomal changes. These genomic alterations may act in concert to dysregulate specific signaling pathways that normally exert their functions on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Targeted therapy against key components of altered signaling pathways has allowed an improvement in CRC treatment. However, there is a significant percentage of CRC and metastatic CRC patients that do not benefit from these targeted therapies, thereby being restricted to systemic chemotherapy. Mechanisms of resistance have been associated with specific gene alterations. To fully understand the nature and significance of the genetic and epigenetic defects in CRC that may favor a tumor to evade a given therapy, much work remains to be done. Therefore, a dynamic link between the basic molecular research and preclinical studies, which ultimately constitute the prelude to standardized therapies, is very important to have better and effective treatments against CRC disease. We present here an updated revision of the main molecular features of CRC and their associated therapies currently underway in clinical trials. Moreover, we performed an unsupervised classification of CRC clinical trials with the aim of obtaining an overview of the future perspectives of preclinical studies.