At the tumor site, solid tumors recruit native and adaptive infiltrating cell subtypes with a unique pattern, varying according to the organ of origin and the stage of the disease, which contributes to the complexity of the cancer microenvironment. The recruitment and activation of immune cells depend on a plethora of soluble immune mediators, including cytokines and chemokines that have a critical role in the process of cancer onset and progression. In colorectal cancer, measurement of soluble immune mediators in the serum seems to reflect the specific inflammatory reaction at the tumor site, and thus they might serve in clinical practice to improve available colorectal cancer detection and screening strategies. Clinical translation of data from experimental models could lead to the earlier detection of colorectal cancer resulting in a decreased burden of metastatic disease. These models and the most promising candidates for immune-based serum screening tests in colorectal cancer are discussed here.