Wars and conflicts in the twenty-first century are putting tremendous strain on the strategies traditionally used by humanitarian responders to help those in need, particularly strategies that deliver effective health responses. Recent civil wars not only account for a larger proportion of ongoing conflicts, but they have become more protracted with more actors with fragmented affiliations. Some of the world’s deadliest places are not formally war zones but areas of extreme political and criminal violence, such as in Venezuela, Mexico, Guatemala, and El Salvador. Providing humanitarian aid amid urban warfare calls for strategies that are different from the ones used in rural settings, where humanitarians have commonly operated in the past. Ruthless deliberate attacks on hospitals, schools, and civilians, as well as sexual and gender-based violence, form part of many of these twenty-first-century conflicts. Humanitarian health workers and health facilities are at growing risk of attack as the normative and legal framework that has traditionally regulated war has become less protective. Geopolitical rivalry and perceptions of a weakening commitment to humanitarian norms are further undermining traditional humanitarian approaches. At the same time, the risk of infectious diseases of pandemic potential intersects with conflict-related health and humanitarian needs, presenting additional challenges for humanitarians.