KRAS genes are the most commonly mutated oncogenes in cancer. Unfortunately, effective therapeutic strategies for targeting KRAS mutant cancers have proven to be difficult to obtain. A key reason for this setback is due to the lack of success direct KRAS mutant inhibitors have received. Researchers have turned their efforts away from targeting the KRAS nucleotide-binding site directly and towards targeting other areas of the MAPK signaling pathway to block KRAS function. Researchers found that inhibiting enzymes and protein-protein interactions involved in the MAPK signaling pathway inhibit the activation of KRAS mutant therefore can lead to a potential therapeutic for KRAS mutated cancers. Throughout the past two decades, various indirect inhibitors have been designed and tested. EGFR and MEK inhibitors have presented with less success; however, significant advances have been made when targeting the plasma membrane localization process and the allosteric site of KRAS mutant. Farnesyltransferase and allosteric inhibitors have both advanced to human clinical trials. This comprehensive review presents the most recent developments of direct and indirect KRAS mutant inhibitors. This review summarizes published data on the inhibitory and anti-cancer activity of compounds that target KRAS activation as well as highlights the most promising strategies for targeting KRAS mutant cancers.