The mitogen-activated protein kinase (MAPK) family is responsible for regulating various intricate cellular processes like cell division cell survival, transformation, migration, cell differentiation, development, and apoptosis. The MAPK super family comprises of four major families, including ERK1/2, JNK, p38, and ERK5. Among the mentioned MAPK families, three families have been characterized which include extracellular signal-regulated kinase (ERK), Jun kinase (JNK/SAPK), and p38 MAPK. These kinases coordinate cellular activities by phosphorylating and modulating the activity of many target proteins involved in transcription, translation, cell cycle, and associated processes. These kinases undergo various genetic and epigenetic modifications which alters the various signaling cascades associated with them leading to cancers and/or inflammatory disorders. Due to the potential of regulating diverse processes within the cell, MAPK inhibitors have drawn a lot of interest as a research tool for figuring out the fundamental principles behind cellular functions as well as a therapeutic tool for treating disorders. In fact, numerous inhibitors against MAP kinases have already been developed. As various malignancies have different ways of primary and secondary signaling and consequently different susceptibility to medicines, it is crucial to understand the diverse ways through which the MAPK/ERK pathway is activated in a particular tumor when devising single and combination drug regimens for its treatment. In this chapter, we highlight the fresh understandings of MAPK as a complex cell signaling pathway involved in maintaining normal cellular function, role in carcinomas, response to chemotherapy, and activating compensatory mechanisms.