An earlier diagnosis is a key strategy for improving the outcomes of patients with cancer. However, achieving this goal can be challenging, particularly for the growing number of people with one or more chronic conditions (comorbidity/multimorbidity) at the time of diagnosis. Pre-existing chronic diseases might affect patient participation in cancer screening, help-seeking for new and/or changing symptoms and clinicians' decision-making on the use of diagnostic investigations. Evidence suggests, for example, that pre-existing pulmonary, cardiovascular, neurological and psychiatric conditions are all associated with a more advanced stage of cancer at diagnosis. By contrast, hypertension and certain gastrointestinal and musculoskeletal conditions might be associated with a more timely diagnosis. In this Review, we propose a comprehensive framework that encompasses the effects of disease-specific, patient-related and health-care-related factors on the diagnosis of cancer in individuals with pre-existing chronic illnesses. Several previously postulated aetiological mechanisms (including alternative explanations, competing demands and surveillance effects) are integrated with newly identified mechanisms, such as false reassurances, or patient concerns about appearing to be a hypochondriac. By considering specific effects of chronic diseases on diagnostic processes and outcomes, tailored early diagnosis initiatives can be developed to improve the outcomes of the large proportion of patients with cancer who have pre-existing chronic conditions.