The notion that stress and cancer are interlinked has dominated lay discourse for decades. More recent animal studies indicate that stress can substantially facilitate cancer progression through modulating most hallmarks of cancer, and molecular and systemic mechanisms mediating these effects have been elucidated. However, available clinical evidence for such deleterious effects is inconsistent, as epidemiological and stress-reducing clinical interventions have yielded mixed effects on cancer mortality. In this Review, we describe and discuss specific mediating mechanisms identified by preclinical research, and parallel clinical findings. We explain the discrepancy between preclinical and clinical outcomes, through pointing to experimental strengths leveraged by animal studies and through discussing methodological and conceptual obstacles that prevent clinical studies from reflecting the impacts of stress. We suggest approaches to circumvent such obstacles, based on targeting critical phases of cancer progression that are more likely to be stress-sensitive; pharmacologically limiting adrenergic–inflammatory responses triggered by medical procedures; and focusing on more vulnerable populations, employing personalized pharmacological and psychosocial approaches. Recent clinical trials support our hypothesis that psychological and/or pharmacological inhibition of excess adrenergic and/or inflammatory stress signalling, especially alongside cancer treatments, could save lives.