Approximately 10% of colorectal cancer (CRC) cases occur in the context of hereditary cancer-predisposing conditions caused by germline pathogenic variants (PVs) in cancer predisposition genes, with Lynch syndrome and familial adenomatous polyposis at the top of the list. Although the identification of hereditary CRC has traditionally relied on clinical characteristics, including familial accumulation, multiple and early onset of CRC and other related cancers, and the presence of gastrointestinal polyposis, more comprehensive approaches, such as universal tumor screening and universal germline testing, have recently been employed. From a technical standpoint, next-generation sequencing has enabled genome-wide analysis of genetic alterations in germline and somatic settings. Taking advantage of this technology, germline multigene panel testing has been utilized in genetic testing, which leads to the identification of PVs, not only in well-known hereditary CRC genes but also in rare causal genes, moderate-risk genes, and high-risk genes previously not linked to CRC predisposition. In addition, comprehensive genomic profiling and companion diagnostics for solid tumors occasionally yield unexpected hereditary CRC diagnoses. Thus, more hereditary CRCs have been identified not based on clinical phenotypes but rather by comprehensive approaches or as secondary findings of treatment drug testing. In this review, we discuss the impact of recent advances in genomic medicine on the clinical aspects of hereditary CRC, which has promoted an understanding of the entire landscape of genetic predisposition to CRC.