About 2000 years ago, Celsus described four of the hallmarks of local inflammation: redness, swelling, heat and pain. In the 19^th century, Virchow added loss of function to the list. However, it was only in 1999 after the description of the first periodic fever syndromes (PFS) that autoinflammatory disorders (AIDs) emerged as a distinct group and more than 40 syndromes have been included under the umbrella of autoinflammation so far. Nevertheless, advancements in the fields of human genetics and basic immunology are often insufficient to establish a definitive diagnosis in up to half of the patients with phenotypes typical of systemic AIDs, resulting in undifferentiated systemic AIDs. Moreover, PFS constitute only a small fraction of the whole universe of autoinflammation and fever is often absent in many systemic AIDs. Therefore, phenotype-guided treatment may be important in many cases of AIDs. In this review, we describe possible cardinal signs of systemic autoinflammation, correlating them with the five cardinal signs of local inflammation originally described by Celsus and Virchow. Five cardinal signs are proposed and specific systemic AIDs are described accordingly: fever, neutrophilic dermatosis, arthritis, panniculitis and sterile osteomyelitis.