Whilst antidepressant medications are widely used, they are ineffective for nearly 40 per cent of users and cause numerous adverse drug reactions. The pharmacogenomics of depression attempts to better understand the role of genetic variation in antidepressant metabolism in the hope of improving drug efficacy and tolerability. In this paper we present findings from a series of focus groups with the general public and with mental health service users in four European sites. Results indicate broad support for genome-based therapies for depression. Findings, however, also show a wide spread of ambivalence regarding the nature and causes of depression, as well as the use of antidepressant medication. We argue that these uncertainties may negatively impact public and user acceptability of the pharmacogenomics of antidepressants.