Purpose: Understanding the place of Ernst von Glasersfeld’s Radical Constructivism (RC), and some of its implications, in the development of epistemology. Design: Characterization of two main options for the content of “knowledge” (without and with belief in mind-independent structures), sketch of their history in occidental thought; comparison of their properties concerning subjectivity, objectivity, second-order cybernetics, reliability of mental tools, and the needs and mechanisms for certainty and overall structures. Findings: Awareness that we structure mental working tools can, as RC suggests, replace belief in mind-independent reality, and this change dissolves the conceptual problem of metaphysics-ontology, but also eliminates the certainty expected from it, which raises the possibility of relativism. Working-concepts cannot be deconstructed because they imply no ontological claims. Subject(s) are necessarily included in all knowledge (which does not mean solipsism): because subjective experience encompasses all mental tools, including those of objectivity and mathematics, while in contrast the subject itself cannot become an objective system. Practical reliability of mental tools differs from subjective certainty, which requires an ontological leap of faith to positive beliefs: for specific tools including automata, and for positive holistic structures. However, in agreement with the constructivist view, holistic views can instead have an unstructured center, with reliability = viability, which prevents relativism. In sum, belief in mid-independent reality is needed for certainty if desired; for all other purposes constructivism is more helpful. Implications: The change in view suggested by von Glasersfeld’s work is of relevance for a number of fields of study with conceptual problems (such as the mind-brain relation). However, due to their generality, the implications will need evaluation in specific instances. The question of certainty needs attention for practical reasons.