The study of medicine taking is controversial as it often reveals a discrepancy between healthcare professionals' advice and patients' actual behaviour. Qualitative researchers have examined depressed people's adherence to prescriptions of antidepressants by exploring the meaning they impute to the medicine and their use of the medicine in the wider context of their everyday lives. This paper contributes to this area of research by means of a prospective research study focussing on depressed patients' perspectives on taking medicine and how they change through time. The study included consecutive semi-structured interviews with 16 people four times during the year following an admission to hospital for depression. Data were collected in 2008-2009 in the Region of Southern Denmark. The study was based on an interactionist conception of social career and data were analysed thematically. Findings indicated that participants were confronted with recurrent challenges related to being depressed and taking medicine, and they learned how to manage these challenges in a post-admission career with two distinct stages: the basic restitution stage and the frustrated search stage. Medicine-taking depended on a number of career moving tensions and problems. The basic restitution stage was characterised by the participants' readiness to take medicine in accordance with healthcare professionals' prescriptions and advice. Half of the participants experienced being challenged by unacceptable prolonged mental, social, and/or physical distress, and they moved to the frustrated search stage, which was characterised by an alternative perspective on taking medicine that included increased self-regulation and less involvement of healthcare professionals and next of kin. Healthcare professionals played a very peripheral role in most participants' lives and unsatisfactory interactions often isolated participants and left them to solve their own problems.