MED12, a critical subunit of the mediator (MED) complex, plays a central role in transcriptional regulation by bridging signal-dependent transcription factors and RNA polymerase II. Dysregulation of MED12, often through mutation, has emerged as a significant driver in various cancers, including uterine leiomyomas, breast cancer (B.C.), and prostate cancer (P.C.). These mutations disrupt normal transcriptional processes by impairing the mediator complex's ability to properly regulate gene expression, which activates oncogenic pathways such as Wnt/β-catenin and TGF-β signaling, promoting tumorigenesis and drug resistance. Specifically, mutations in the MED12 gene lead to altered interactions with the transcriptional machinery, fostering aberrant activation of oncogenic networks. MED12 alterations have also been implicated in chemoresistance, particularly to therapies targeting EGFR, ALK, and BRAF, highlighting its role as a barrier to effective treatment. This review explores the mechanisms underlying MED12 dysregulation, its impact on cancer progression, and its association with therapeutic resistance. By examining its potential as a predictive biomarker and a therapeutic target, the article underscores the importance of MED12 in advancing precision oncology. Understanding MED12-mediated mechanisms offers insights into overcoming therapeutic resistance and paves the way for innovative, personalized cancer treatments.