Metagenomics is increasingly used for diagnosis in hospital settings. It is useful particularly in cases of unknown aetiology, where novel or difficult-to-diagnose pathogens are suspected, and/or following unexplained disease outbreaks. In this paper, we present three use cases that draw on existing reports: one involving a patient in intensive care with encephalitis of unknown aetiology; a second case with likely infection with drug-resistant Klebsiella pneumoniae and an incidental finding of unknown relevance; and a third case situated in an unexplained outbreak of acute hepatitis in children, with severe outcomes due to co-infection. We examine each case in turn, highlighting ethical questions arising in relation to clinical issues including: disclosure to patients of untreatable disease, cost-effectiveness, the value of resistance testing, sensitivity and specificity, uncertain or unexpected findings, patient consent and data sharing. We conclude by proposing recommendations for further research and developing particular pieces of guidance to improve clinical uses of metagenomics for diagnosis.