In this review, we have reviewed the general properties and the transcriptional and post-transcriptional regulations of RKIP and PTEN in cancer and their roles in the regulation of both chemo- and immune-resistance, the various cross-talk signaling pathways shared by RKIP and PTEN, bioinformatic analyses exploring the cross-talk pathways between RKIP and PTEN gene products, and the therapeutic implications of these new findings. The gene discussed is PEBP1; the disease is cancer.