Homelessness is a growing problem. These people face huge inequalities and frequent hospitalizations, often lacking social support. The condition is one of extreme poverty and affects public health care costs. The risk of mortality and morbidity is high. Together with the synergy between health care institutions and targeted policies, Third Sector Associations are fundamental. The nurse is crucial in responding to the needs of the most fragile individuals by ensuring an integrated approach to care. The Como Services for Serious Marginalization are concerned with taking charge of and satisfying the needs of homeless people through the services provided also in the current pandemic. The main exigencies that emerge are hospitality, active listening and the need for primary services. Both Italian and immigrant populations are represented. The realities involved rely on the figure of the nurse both directly and indirectly. The health inequity faced by the homeless requires special attention. The homelessness needs require an integrated service model with reorganization needed due to the ongoing pandemic. The Nurse can become central to the territorial management of frailty and social vulnerabilities.