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Summary: Since the nineties, the incidence of sporadic early-onset (EO) cancers has been rising worldwide. The underlying reasons are still unknown. However, identifying them is vital for advancing both prevention and intervention. Here, we exploit available knowledge derived from clinical observations to formulate testable hypotheses aimed at defining the causal factors of this epidemic and discuss how to experimentally test them. We explore the potential impact of exposome changes from the millennials to contemporary young generations, considering both environmental exposures and enhanced susceptibilities to EO-cancer development. We emphasize how establishing the time required for an EO cancer to develop is relevant to defining future screening strategies. Finally, we discuss the importance of integrating multi-dimensional data from international collaborations to generate comprehensive knowledge and translate these findings back into clinical practice.