<p>Early-onset cancer (EOC) of the oesophagus, stomach, colorectum, biliary tract, liver, pancreas, kidney, prostate, uterine corpus, breast, bone marrow, and head and neck has shown an increasing incidence worldwide. This Review summarizes current evidence for epidemiological and molecular pathological features of rising EOC overall and in each organ-specific cancer type, underscoring not only their shared aetiologies but also their dissimilarities. Although the contributions of enhanced screening, diagnostics and early detection to the rise of EOC are difficult to quantify, a genuine increase in EOC development seems likely in certain EOC types exhibiting mortality increases or aggressive tumoural features compared to later-onset counterparts. Evidence suggests that this trend reflects decades-long influences of environmental, lifestyle, systemic and metabolic factors that begin in early life. Polygenic influences with associated gene–environment interactions on cancer risks appear more pronounced in younger ages. However, identifying specific aetiological factors remains difficult due to prolonged latency, confounding and limited availability of long-term exposure data. Nonetheless, EOC tumour profiling efforts provide pathogenic clues to genomic, epigenomic, microbial and immune contributions. Integrative research frameworks, such as molecular pathological epidemiology, combined with the prospective cohort incident-tumour biobank method, comprehensive biorepositories and artificial intelligence-empowered analytical tools, offer promising opportunities to clarify pathophysiological mechanisms.</p>