Dysbiosis of gut microbiome can contribute to inflammation, and subsequently initiation and progression of colorectal cancer (CRC). Throughout these stages, various proteins and metabolites are secreted to the external environment by microorganisms or the hosts themselves. Studying these proteins may help enhance our understanding of the host-microorganism relationship or they may even serve as useful biomarkers for CRC. However, secretomic studies of gut microbiome of CRC patients, until now, are scarcely performed. In this review article, the focus is on the roles of gut microbiome in CRC, the current findings on CRC secretome are highlighted, and the emerging challenges and strategies to drive forward this area of research are addressed.