Practice-Based Research Network (PBRN) studies typically assess the effectiveness of clinical interventions in settings that match real-world conditions. Dental PBRNs have the capacity to amass, identify, and analyze vast amounts of data from patient populations that include diverse racial, ethnic, socio-economic, and geographic backgrounds. These dental studies encompass a broad spectrum of healthcare aspects, including prevention, diagnosis, symptom and disease treatment, quality enhancement, and care coordination. An extensive range of research methodologies can be employed within dental PBRNs to investigate these topics, including randomized controlled trials. Dental PBRNs have evolved from primarily focusing on case observations to leveraging advanced network infrastructure and collaborating across multiple regional and national sites. In addition to producing numerous high-impact peer-reviewed publications, study results have led to improved clinical care. However, PBRNs encounter challenges, such as the sustainability of research capacity (relying heavily on ongoing support from funding agencies), diverse research cultures, and an imperative to design studies that are both feasible and relevant to everyday clinical practice. Recognizing the pivotal role of real-world evidence, it is important to have sustained investment in dental PBRN infrastructure and feasible opportunities for practitioners to participate in network activities nationwide. Practice-Based Research Network studies capitalize on an important research context within which to investigate a range of clinical topics that can employ multiple research methodologies. However, sustaining productive networks requires strategic effort, ongoing financial support, and customized organizational skills.