Objective Persons experiencing homelessness (PEH) are among the most vulnerable populations and experience significant health disparities. Nationally, PEH utilize Emergency Medical Services (EMS) at disproportionately higher rates than their housed peers. Developing optimal strategies to care for PEH has become critically important. However, limited data exists on best practices, challenges, and experiences of providing care to PEH. The objective of this study was to describe the experiences, challenges and perspectives of operational EMS agency medical directors in Los Angeles (LA) County as they confront the homelessness crisis. Methods We performed a cross-sectional survey of 9-1-1 operational EMS agency medical directors in LA County, which has one of the largest populations of PEH nationally. Twenty-nine 9-1-1 operational EMS agencies operate in LA County. The link to an anonymous, web-based survey examining documentation, training, resources, operational impact, and care challenges was emailed to medical directors with three reminders during the study period (4/19/2023-9/15/2023). Results Three quarters (75.9%; 22/29) of operational EMS agencies responded to the survey, with all questions answered in 69% (20/29) of surveys. Of these, 68.2% (15/22) of agencies document housing status and 75% (15/20) agreed or strongly agreed that homelessness presents operational challenges. No operational EMS agency reported adequate EMS clinician training on homelessness. Operational EMS agencies most commonly utilized domestic violence resources (43%, 9/21), social services (38%, 8/21), and law enforcement (38%, 8/21) services to assist PEH. Referrals were limited by accessibility (86%, 18/21), time (52%, 11/21), lack of awareness (52% 11/21) and lack of mandates (52%, 11/21). All operational EMS agencies agreed or strongly agreed that mental health and substance use disorders are major issues for PEH. The most common daily challenges reported were mental health (55%, 11/20), substance use (55%, 11/20), and patient resistance (35%, 7/20). Conclusion In LA County, EMS agencies experience important operational and clinical challenges in caring for PEH, with limited resources, minimal training, and high rates of substance use disorders and mental health comorbidities. Further prehospital research is essential to standardize documentation of housing status, to identify areas for intervention, increase linkage to services, and define best practices.