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To ask, with Hamlet, the deceptively simple question 'what is the cause?', is, as this study demonstrates, to get to the heart of some of the early-modern period's most resonant, far-reaching, and contested topics. It is a question that informs everything from the largest metaphysical enquiries to the tiniest instances of particulate physics, asking what this study shows to be one of the most pertinent questions of a philosophically ambitious, intellectually aspirational, theologically destabilized age. Taking King Lear as its focus, this book situates Shakespeare and his world-weary tragedy at the intersection of major epistemic trajectories in philosophical, religious, and scientific thought. Shakespeare's play, it argues, was produced at a crisis-point, a crux at which confidence in an older metaphysical order was being incrementally eroded, and was yet to be recuperated by the advent of the 'new' physics and later natural-scientific philosophies. Shakespeare writes, in short, at a moment of profound causal uncertainty, conscious of cultural change, and yet not confident of the wisdom of his age's purported progress. Consequently, King Lear is shown to be a play riven by causal scepticism and deep-seated intellectual doubt, in which Shakespeare cycles through a rich array of classical analogues, philosophical influences, biblical sources, and literary intertexts, finding each unfit for the Machiavellian machinations and politic purposes of an incipient modern age. This ambitious and far-reaching study offers a new understanding of Shakespeare's philosophical underpinnings, illuminating his active, informed participation in an aetiological debate that should be understood as the key epistemological enquiry of his time.