ERK1 and ERK2 are key protein kinases that contribute to the Ras-Raf-MEK-ERK MAP kinase signalling module. This pathway participates in the control of numerous processes including apoptosis, cell proliferation, the immune response, nervous system function, and RNA synthesis and processing. MEK1/2 activate human ERK1/2 by first catalyzing the phosphorylation of Y204/187 and then T202/185, both residues of which occur within the activation segment. The phosphorylation of both residues is required for enzyme activation. The only Raf substrates are MEK1/2 and the only MEK1/2 substrates are ERK1/2. In contrast, ERK1/2 catalyze the phosphorylation of many cytoplasmic and nuclear substrates including transcription factors and regulatory molecules. The linear MAP kinase pathway branches extensively at the ERK1/2 node. ERK1/2 are proline-directed kinases that preferentially catalyze the phosphorylation of substrates containing a PxS/TP sequence. The dephosphorylation and inactivation of ERK1/2 is catalyzed by dual specificity phosphatases, protein-tyrosine specific phosphatases, and protein-serine/threonine phosphatases. The combined functions of kinases and phosphatases make the overall process reversible. To provide an idea of the complexities involved in these reactions, somatic cell cycle progression involves the strict timing of more than 32,000 phosphorylation and dephosphorylation events as determined by mass spectrometry. The MAP kinase cascade is perhaps the most important oncogenic driver of human cancers and the blockade of this signalling module by targeted inhibitors is an important anti-tumor strategy. Although numerous cancers are driven by MAP kinase pathway activation, thus far the only orally effective approved drugs that target this signaling module are used for the treatment of BRAF-mutant melanomas. The best treatments include the combination of B-Raf and MEK inhibitors (dabrafenib and trametinib, encorafenib and binimetinib, vemurafenib and cobimetanib). However, resistance to these antagonists occurs within one year and additional treatment options are necessary. Owing to the large variety of malignancies that are driven by dysregulation of the MAP kinase pathway, additional tumor types should be amenable to MAP kinase pathway inhibitor therapy. In addition to new B-Raf and MEK inhibitors, the addition of ERK inhibitors should prove helpful. Ulixertinib, MK-8353, and GDC-0994 are orally effective, potent, and specific inhibitors of ERK1/2 that are in early clinical trials for the treatment of various advanced/metastatic solid tumors. These agents are effective against cell lines that are resistant to B-Raf and MEK1/2 inhibitor therapy. Although MK-8353 does not directly inhibit MEK1/2, it decreases the phosphorylation of ERK1/2 as well as the phosphorylation of RSK, an ERK1/2 substrate. The decrease in RSK phosphorylation appears to be a result of ERK inhibition and the decrease in ERK1/2 phosphorylation is related to the inability of MEK to catalyze the phosphorylation of the ERK–MK-8353 complex; these decreases characterize the ERK dual mechanism inhibition paradigm. Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway.