Interest is rapidly growing around screening for health-related social needs (HRSN) in direct patient care settings. The screening and provision of HRSN is often done in the context of trying to address social determinants of health. While there is emerging evidence that screening and referral for HRSN can improve health outcomes, there are educational, operational, and systemic gaps that need to be filled in order for HRSN screening and referral to be implemented system-wide and result in meaningful improvement in population health outcomes. The American College of Preventive Medicine recommends HRSN screening and referral in patient care settings only when there are sufficient systems in place to support addressing those needs. This paper identifies key considerations to take into account when implementing HRSN screening and referral in healthcare settings and makes recommendations to address those key considerations. The recommendations also frame the broader need to address social determinants of health at a population level. Finally, the paper identifies several knowledge and evidence gaps in the existing literature on the topic of HRSN, which will hopefully drive future research in this area, and result in an evidence-based, population approach to the issue.