The UK Health Security Agency (UKHSA) is set for two major leadership transitions, four years after its establishment. Dame Jenny Harries has announced she will step down as UKHSA chief executive in early summer. Meanwhile, UKHSA’s chief scientific officer, Professor Isabel Oliver, has been appointed chief medical officer for Wales, succeeding Sir Frank Atherton following his retirement. Appointed in April 2021 as UKHSA’s first chief executive, Dame Jenny played a pivotal role in creating the agency during the COVID-19 pandemic. Under her leadership, UKHSA developed specialist scientific, data, and operational expertise to safeguard the public from infectious diseases and other health threats. Reflecting on her tenure, Dame Jenny expressed immense pride in UKHSA’s early achievements.