Aberrant activation of the PI3K Akt pathway that is thought to be an important component causing the insensitivity of cancer cells to chemotherapy, is implicated in many cancers through many molecular mechanisms. Nevertheless, cumulative data indicated that as well as intrinsic drug Lapatinib EGFR inhibitor resistance, chemotherapy induced resistance might occur either by service of the PI3K Akt pathway and/or via the regulation of MDR efflux transporters of the ABC superfamily. Ergo, the ABC superfamily of MDR transporters and components of the PI3K Akt pathway are fundamental targets for chemotherapy. In this respect, it had been previously recognized a drug combination method is required for successful chemotherapy. Certainly, many drug mixture techniques have been studied, incorporating traditional chemotherapy with PI3K Akt path inhibitors including LY294002 and wortmannin, Akt inhibitors perifosine and triciribine, and mTOR inhibitor rapamycin and its analogues have been investigated extensively in preclinical studies thereby showing a efficacy in vivo. Our current studies indicated that mixing the Akt pathway chemical LY294002 with conventional chemotherapeutics including MR and topotecan, elicited an amazing synergistic effect, thereby increasing the cytotoxic efficacy of the anticancer drugs therapy. Ergo, these encouraging in-vitro studies could be easily translatable to Ribonucleic acid (RNA) preclinical in vivo studies. An alternative method mixing pathway inhibitors with other targeted therapies involves inhibition of proximal pathway factors such as receptor tyrosine kinases and oncogenes, combined with downstream inhibition of Akt or mTOR. This was proposed as a successful means of circumventing feedback service that could happen with downstream inhibition alone. Small molecule inhibitors of EGFR tyrosine kinase including gefitinib and erlotinib that are FDA approved drugs, also have shown promising clinical activities when combined with traditional chemotherapeutics. Nevertheless, acquired drug resistance to TKIs is associated with increased expression of ABCG2, which often leads to efflux of TKIs from cancer cells. Instead, dual inhibition of similar signaling pathways stops compensatory activation of obsolete professional survival pathways. AP26113 Finally, inhibition of signaling pathways can be coupled with various other forms of targeted therapeutics including inhibition of histone deacetylase complexes or proteasome inhibitors. In conclusion, in line with the multifactorial nature of MDR and the frequent failure of clinical efforts to defeat MDR, we suggest that as a way to increase treatment effectiveness towards the ultimate purpose of overcoming MDR, rationally developed, specific synergistic combinations of chemotherapeutic drugs are highly needed.