A promising new era of cancer therapeutics with agents that inhibit specific growth stimulatory pathways is finding a new niche in our armamentarium in the war against cancer. Targeted cancer therapeutics, including humanized monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are amongst the major treatment options for cancer today together with cytotoxic chemotherapies. Targeted therapies are more selective for cancer cells and improve the quality of life for cancer patients undergoing treatment. Many of these drugs have been approved by the FDA, and several more are being studied in clinical trials. Although development of targeted therapeutics has improved cancer treatment significantly, the harsh reality is that the "War on Cancer" still exists. Major challenges still exist with the currently marketed inhibitors, including limitations associated with mAbs and TKIs drug types, acquired mechanisms of drug resistance that cause patient relapse, and tumor heterogeneity. Today, there is an urgent need for the development of novel anti-tumor agents that are cheaper, stable, can selectively target cancer dependent pathways without affecting normal cells, and most importantly, avoid development of resistance mechanisms. Peptide mimics have the potential benefits of being highly selective, stable, cheap, and non-toxic. The focus of this review is to discuss the disadvantages associated with the use of monoclonal antibodies and tyrosine kinase inhibitors. A special emphasis will be placed on efforts taken in our laboratory to 1) design peptide vaccines and therapeutics that target cancer dependent pathways and 2) use a combination approach that will shut down alternative mechanisms that lead to resistance.