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Diverse and non-coherent sets of epistemological principles currently inform research in the general area of functional genomics. Here, from the personal point of view of a scientist with over half a century of immersion in hypothesis driven scientific discovery, I compare and deconstruct the ideological bases of prominent recent alternatives, such as “discovery science,” some productions of the ENCODE project, and aspects of large data set systems biology. The outputs of these types of scientific enterprise qualitatively reflect their radical definitions of scientific knowledge, and of its logical requirements. Their properties emerge in high relief when contrasted (as an example) to a recent, system-wide, predictive analysis of a developmental regulatory apparatus that was instead based directly on hypothesis-driven experimental tests of mechanism.