Colorectal cancer (CRC) is the second most diagnosed disease worldwide. It is the fourth leading cause of cancer related mortalities. Higher probability for the occurrence of CRC is due to western lifestyle, age, and personal history of chronic diseases. The development of CRC is a multistep process that includes a sequence of genetic, histological, and morphological alterations that accumulate over time. Furthermore, depending on the origin of mutations, CRC can be classified as familial, sporadic, and inherited, based on which a therapeutic plan is created for a CRC patient. These mutations cause chromosomal alterations and translocations in genes that lead to microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and chromosomal instability (CIN). The mutations affect dysregulation of various pathways that are responsible for cancer progression. They include the PI3K/Akt, Wnt, TP53, and MAPK pathways. Mutated genes, such as KRAS, PTEN, SMAD4, BRAF, and PTEN, are employed as predictive biomarkers for early diagnosis. The conventional therapies of CRC start with surgical resection followed by adjuvant therapies, such as radiotherapy and chemotherapy. Researchers are now developing therapies that combine triplet drugs to overcome the hurdle of multidrug resistance (MDR). The combination of chemotherapy with immunotherapy to target the dysregulated proteins, such as EGFR and VEGFR is found efficient for advanced mCRC therapy. Researchers are now developing personalized medicines by detecting and validating key biomarkers to understand the mechanism of MDR and toxicity. In this review, we address genetic alterations, current data on biomarkers, and novel therapeutic approaches for the treatment of CRC.