<jats:title>Summary</jats:title><jats:p>Immunological memory provides rapid protection to pathogens previously encountered through infection or vaccination. <jats:styled-content style="fixed-case">CD</jats:styled-content>4 T‐cells play a central role in all adaptive immune responses. Vaccines must, therefore, activate <jats:styled-content style="fixed-case">CD</jats:styled-content>4 T‐cells if they are to generate protective immunity. For many diseases, we do not have effective vaccines. These include human immunodeficiency virus (<jats:styled-content style="fixed-case">HIV)</jats:styled-content>, tuberculosis and malaria, which are responsible for many millions of deaths each year across the globe. <jats:styled-content style="fixed-case">CD</jats:styled-content>4 T‐cells play many different roles during the immune response coordinating the actions of many other cells. In order to harness the diverse protective effects of memory <jats:styled-content style="fixed-case">CD</jats:styled-content>4 T‐cells, we need to understand how memory <jats:styled-content style="fixed-case">CD</jats:styled-content>4 T‐cells are generated and how they protect the host. Here we review recent findings on the location of different subsets of memory <jats:styled-content style="fixed-case">CD</jats:styled-content>4 T‐cells that are found in peripheral tissues (tissue resident memory T‐cells) and in the circulation (central and effector memory T‐cells). We discuss the generation of these cells, and the evidence that demonstrates how they provide immune protection in animal and human challenge models.</jats:p>