Abstract Background Massively-parallel sequencing (MPS) technologies create challenges for informed consent of research participants given the enormous scale of the data and the wide range of potential results. Discussion We propose that the consent process in these studies be based on whether they use MPS to test a hypothesis or to generate hypotheses. To demonstrate the differences in these approaches to informed consent, we describe the consent processes for two MPS studies. The purpose of our hypothesis-testing study is to elucidate the etiology of rare phenotypes using MPS. The purpose of our hypothesis-generating study is to test the feasibility of using MPS to generate clinical hypotheses, and to approach the return of results as an experimental manipulation. Issues to consider in both designs include: volume and nature of the potential results, primary versus secondary results, return of individual results, duty to warn, length of interaction, target population, and privacy and confidentiality. Summary The categorization of MPS studies as hypothesis-testing versus hypothesis-generating can help to clarify the issue of so-called incidental or secondary results for the consent process, and aid the communication of the research goals to study participants.