Personalized medicine is defined by therapy decisions tailored to individual patients, aiming to improve therapeutic efficiencies and to minimize side effects. The current clinical practice includes targeted therapies for disease-related alterations and molecular biomarker-based patient stratification. However, recent advances in screening technologies have enabled more comprehensive identification strategies and suggest a plethora of additional valuable biomarkers and druggable molecules for future clinical applications. Beside genetic alterations, in particular, DNA methylation biomarkers emerge into the field by presenting stable DNA modifications with predictive potential for drug treatment efficiencies, especially in a cancer context. Although not directly affecting the genetic code, DNA methylation exhibits regulatory functions with high impact on disease onset and progression. In this article, the authors summarize the current knowledge of DNA methylation biomarkers for treatment efficiencies and evaluate their translational value into clinical use.