Infectious diseases remain major public health challenges in the United States, according to a new report published in The Lancet as part of a new Series, The health of Americans . Endemic conditions such as chronic viral hepatitis, human immunodeficiency virus, and other sexually transmitted infections continue to affect millions of individuals, with racial and ethnic minorities disproportionately affected. Emerging and re-emerging vector borne and zoonotic disease infections are threatening new areas and populations, as most recently observed with Chikungunya. Despite major prevention gains, cases and outbreaks of vaccine-preventable diseases persist, due to factors such as disease importation, parental decisions to withhold or delay vaccination, and waning vaccine-induced immunity. In 2014, US outbreaks of measles, largely associated with travel, have resulted in the largest number of cases since the disease was declared eliminated in the United States in 2000. Other priority areas for new prevention strategies include foodborne diseases and healthcare-associated infections. Antimicrobial resistance is a global health crisis, demanding new approaches and collaborations for prevention and control. Improved pathogen understanding afforded by genomic testing and other technologies, along with increased recognition of the importance and role of the human microbiome, are offering new opportunities to reduce infectious diseases.