Developments in public health genomics (PHG) hold the promise to be beneficial for individuals and to promote public health. Central to this paper is the idea that given the range of uncertainties and ambiguities related to genome-based information and technologies (GBIT), the responsible introduction of GBIT in health care systems requires an incremental approach. The paper highlights policy issues connected to two major shifts connected to developments in PHG that challenge traditional boundaries. First, the introduction of GBIT in health care systems challenges the boundary between research and clinical care. It entails complex data flows that raise a number of issues relating to infrastructural demands, intellectual property, data security and privacy, tensions between the needs of research and the needs of the individual, patient rights and professional responsibilities, and the potential feedback of (re)analysed data. Secondly, the introduction of GBIT in health care systems challenges the boundary between clinical care (particularly diagnostics) and screening. Both diagnostics and screening involve potentially large amounts of information about an individual’s genome, and raise new and challenging issues concerning quality assessment and how to deal with unsolicited information that might be generated from these tests. These issues could arise in a variety of health care settings in which whole genome sequencing tests find further application in established and new practices of diagnostics and screening. The possibility of screening the whole genome raises the question of what to screen for and when, and whether existing evaluative frameworks – concerning quality assessment and ethical and legal aspects of GBIT – are robust enough, or require fine-tuning. These shifts have implications for the relations between all stakeholders. The responsible introduction of GBIT in the health care system thus requires an early dialogue in which these stakeholders are actively involved.