The article discusses the role of pioneer transcription factors in establishing competence for gene expression in eukaryotic cells. These factors, such as FoxA and GATA, can access and bind to DNA sequences within condensed chromatin, which is often occluded by histones and higher-order chromatin structures. This initial binding can enhance transcription by reducing the number of additional factors needed to bind the DNA and can also actively open up the local chromatin, making it more accessible to other factors. The authors review the mechanisms by which pioneer factors achieve this, including their ability to bind nucleosomes and compacted chromatin, and their role in various developmental processes and diseases, such as embryonic development, steroid hormone induction, and human cancers. They also explore the potential of pioneer factors as therapeutic targets in cancer, particularly in hormone-driven solid tumors like breast and prostate cancer.The article discusses the role of pioneer transcription factors in establishing competence for gene expression in eukaryotic cells. These factors, such as FoxA and GATA, can access and bind to DNA sequences within condensed chromatin, which is often occluded by histones and higher-order chromatin structures. This initial binding can enhance transcription by reducing the number of additional factors needed to bind the DNA and can also actively open up the local chromatin, making it more accessible to other factors. The authors review the mechanisms by which pioneer factors achieve this, including their ability to bind nucleosomes and compacted chromatin, and their role in various developmental processes and diseases, such as embryonic development, steroid hormone induction, and human cancers. They also explore the potential of pioneer factors as therapeutic targets in cancer, particularly in hormone-driven solid tumors like breast and prostate cancer.