We reviewed the first 21 years (1991–2011) of Australia's National Notifiable Diseases Surveillance System (NNDSS). All nationally notified diseases (except HIV/AIDS and Creutzfeldt–Jakob disease) were analysed by disease group (n = 8), jurisdiction (six states and two territories), Indigenous status, age group and notification year. In total, 2 421 134 cases were analysed. The 10 diseases with highest notification incidence (chlamydial infection, campylobacteriosis, varicella zoster, hepatitis C, influenza, pertussis, salmonellosis, hepatitis B, gonococcal infection, and Ross River virus infection) comprised 88% of all notifications. Annual notification incidence was 591 cases/100 000, highest in the Northern Territory (2598/100 000) and in children aged <5 years (698/100 000). A total of 8·4% of cases were Indigenous Australians. Notification incidence increased by 6·4% per year (12% for sexually transmissible infections and 15% for vaccine-preventable diseases). The number of notifiable diseases also increased from 37 to 65. The number and incidence of notifications increased throughout the study period, partly due to addition of diseases to the NNDSS and increasing availability of sensitive diagnostic tests. The most commonly notified diseases require a range of public health responses addressing high-risk sexual and drug-use behaviours, food safety and immunization. Our results highlight populations with higher notification incidence that might require tailored public health interventions.