Helping students better understand how scientists reason and argue to draw scientific conclusions has long been viewed as a critical component of scientific literacy, thus remains a central goal of science instruction. However, differences of opinion persist regarding the nature of scientific reasoning, argumentation, and discovery. Accordingly, the primary goal of this paper is to employ the inferences of abduction, retroduction, deduction, and induction to introduce a pattern of scientific reasoning, argumentation, and discovery that is postulated to be universal, thus can serve as an instructional framework to improve student reasoning and argumentative skills. The paper first analyzes three varied and presumably representative case histories in terms of the four inferences (i.e., Galileo's discovery of Jupiter's moons, Rosemary and Peter Grants' research on Darwin's finches, and Marshall Nirenberg's Nobel Prize–winning research on genetic coding). Each case history reveals a pattern of reasoning and argumentation used during explanation testing that can be summarized in an If/then/Therefore form. The paper then summarizes additional cases also exemplary of the form. Implications of the resulting theory are discussed in terms of improving the quality of research and classroom instruction. © 2009 Wiley Periodicals, Inc. Sci Ed94:336–364, 2010