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A hallmark of MAPK signaling is their nuclear translocation upon stimulation, which is necessary for their physiological/pathological functions. We have identified two novel, distinct, regulated nuclear translocation mechanisms for ERK1/2 and JNK/p38, of which we made use of as a promising therapeutic approach. We developed a myristoylated, NTS-derived phosphomimetic peptide (EPE peptide), which blocked ERK1/2 nuclear translocation. In culture, the EPE peptide induced apoptosis of melanoma cells, inhibited the proliferation of other cancer cells but had no effect on immortalized cells. Combination of the EPE peptide and the MEK inhibitor had synergistic antitumor activity in mutated NRAS, BRAF and NF1 melanoma and Kras pancreatic cells. In xenograft models, the peptide was significantly more effective than BRAF inhibitors in preventing tumor recurrence of treatment-eradicated melanoma xenografts. We also developed p38-derived myristoylated peptide, termed PERY peptide, which inhibited the importin interaction with JNK1/2 and p38α/β and prevented their nuclear translocation. This peptide affected viability of several breast cancer-derived cell lines, and significantly reduced inflammation and intestinal damage in a mouse model of colitis. Moreover, the peptide inhibited inflammation-induced colorectal cancer in a AOM/DSS mouse model. Taken together, both the cancer and inflammatory models support the use of nuclear translocation of MAPKs as a novel drug target for signaling-related diseases.