Transcriptional regulators include a superfamily of nuclear proteins referred to as co-activators and co-repressors, both of which are involved in controlling the functions of several nuclear receptors (NRs). The Nuclear Receptor Signaling Atlas (NURSA) has cataloged the composition of NRs, co-regulators, and ligands present in the human cell and their effort has been identified in more than 600 potential molecules. Given the importance of co-regulators in steroid, retinoid, and thyroid hormone signaling networks, hypothesizing that NRs/co-regulators are implicated in a wide range of pathologies are tempting. The co-activators known as peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1) and their key nuclear partner, the estrogen-related receptor (ERR), are emerging as pivotal transcriptional signatures that regulate an extremely broad repertoire of mitochondrial and metabolic genes, making them very attractive drug targets for cancer. Several studies have provided an increased understanding of the functional and structural biology of nuclear complexes. However, more comprehensive work is needed to create different avenues to explore the therapeutic potential of NRs/co-activators in precision oncology. Here, we discuss the emerging data associated with the structure, function, and molecular biology of the PGC-1/ERR network and address how the concepts evolving from these studies have deepened our understanding of how to develop more effective treatment strategies. We present an overview that underscores new biological insights into PGC-1/ERR to improve cancer outcomes against therapeutic resistance. Finally, we discuss the importance of exploiting new technologies such as single-particle cryo-electron microscopy (cryo-EM) to develop a high-resolution biological structure of PGC-1/ERR, focusing on novel drug discovery for precision oncology.