All biological processes, from embryonic development to cancer, are tightly controlled by the interactions between genetics and epigenetics. An array of epigenetic modifications, such as DNA methylation, histone/chromatin modifications, and noncoding RNA-mediated targeting, are essential to regulate the heritable changes that occur during multiple cellular processes. A failure in proper regulation results in inappropriate gene expression that ultimately leads to pathological states. Groundbreaking advances in genomics and transcriptomics have revealed the potential involvement of epigenetics in various physiological and pathological states. The promising clinical and preclinical results shown by epigenetics drugs further underscore the central role of epigenetics in multiple human diseases, including cancer. AT rich interaction domain (ARID)-containing proteins are a family of evolutionarily conserved DNA binding proteins that regulate epigenetic modifications. Genome sequencing has revealed the existence of 15 ARID family proteins that are divided into 7 subfamilies based on their sequence and domain homology. Although the ARID family of proteins are implicated in cell growth, development, differentiation, and cancer, the diverse biological functions of many family members remain to be elucidated. Here, we focus on ARID4B to summarize its prominent role in embryonic stem cell differentiation and human malignancies.