Metastatic colorectal cancer is a prevalent disease for which novel targeted therapies and biologically based combinations are under development. Cytotoxic chemotherapy doublets (FOLFOX, FOLFIRI) and triplets (FOLFOXIRI) in combination with biologics are standard regimens, and efforts are ongoing to delineate the optimal sequence for each patient based on unique underlying tumor biology. Molecular profiling of metastatic colorectal cancer (including mutational analysis for KRAS, NRAS, BRAF, PIK3CA, and others) has become increasingly important for identification of prognostic and predictive biomarkers, as well as for insights into the biology that drives the tumor. Large comprehensive analyses such as that of The Cancer Genome Atlas have provided important clues into carcinogenesis and discerned potentially druggable targets for metastatic colorectal cancer. Novel therapeutic agents currently under investigation for subtypes of this disease include immunotherapies such as anti-programmed cell death receptor antibody, cancer stem cell inhibitors, targeted combinations such as BRAF and PI3K inhibitors, and the anti-RAS reovirus Reolysin®.