In Book I of the Treatise, Hume advanced the startling notion that ‘All the sciences have a relation, greater or less, to human nature; and that however wide any of them may seem to run from it, they still return back by one passage or another.’ Contrary to Locke, then, for whom philosophy was understood as the under-labourer of natural science, Hume maintains that the science of humanity is logically prior to any other science.

Unlike Descartes, Malebranche and Berkeley, Hume wished to root philosophy in human experience and do so in a way that both acknowledged the limits of reason and eschewed metaphysical posits such as ‘spirit’ or ‘God’. ‘When we see, that we have arrived at the utmost extent of human reason, we sit down contented; tho' we be perfectly satisfied in the main of our ignorance, and perceive that we can give no reason for our most general and most refined principles, beside our experience of their reality.’

Hume wished to produce a secular philosophy in the tradition of Newton, Shaftesbury, Mandeville, Hutcheson and Butler. As a sceptic, however, Hume never lost sight of the fact that nature itself is only grasped through human life and experience, and it remained for him doubtful as to whether human experience is actually able to yield knowledge.

The third book of Hume's Treatise, ‘Of Morals’, was published in 1740. Rather than appealing to a divine basis for morality, Hume instead looked only to humanity's animal capacity for ‘sympathy’ and upon the universalizing ‘moral sentiment’. Adam Smith would follow a similar line of thought in his Theory of the Moral Sentiments (1759). It is a strategy that militates against Christian and rationalistic efforts, including those of Descartes and Locke, to deploy reason or revelation in the establishment of moral norms.

Hume's moral theory also rejects the egoistic naturalism developed by Hobbes and Mandeville, which explains apparently altruistic acts as really expressions of self-interest. Hume accepted the naturalistic, sentimental basis for morality developed by the egoists but sought to mitigate, if not wholly undermine, it by maintaining that the natural capacity for sympathy extends human concern beyond the immediate self. In many such instances, concern for one's own feelings of pleasure and pain converge with universal regard for others.

In 1752 Hume published the Political Discourses. This text, together with his other popular essays, would catapult Hume into the intellectual limelight. In 1754 Hume began publishing his History of England, a series of volumes which would secure his standing in Europe. Across the Atlantic Hume's work was influential with many, including Benjamin Franklin, Alexander Hamilton, and quite possibly James Madison.

Hume was, however, less well received among the religious. He was denied several academic posts, and the General Assembly of the Church of Scotland considered formally prosecuting Hume in 1755 and 1756. Hume suppressed many of his writings out of concern for reprisals, including his posthumous Dialogues concerning Natural Religion (1779), a text that advances perhaps the most powerful arguments ever launched against natural theology and the argument from design.

In 1763 Hume assumed the position of private secretary to the British ambassador to France, a post which brought him into contact with many important French intellectuals, including d'Alembert, Buffon, Diderot, Turgot, Helvétius, and d'Holbach. The Scotsman found himself, however, at times disaffected among the philosophes, discovering his sceptical reserve to be as inconsistent with their dogmatic atheism and deism as it had been with dogmatic Christianity in Britain.

In the latter part of 1765, Hume helped Rousseau to flee Switzerland and France, where he had been prosecuted for sedition and impiety, for the protection of England. Rousseau, however, came to believe that Hume was in league with his enemies and broke off all connection with him.

Hume died at approximately four o'clock in the afternoon on 25 August 1776 in Edinburgh. As his death approached, crowds gathered to see whether or not he would embrace Christianity in his last moments. James Boswell recounts that Hume ‘said he never had entertained any belief in Religion since he began to read Locke and Clarke … He then said flatly that the Morality of every Religion was bad, and, I really thought, was not jocular when he said “that when he heard a man was religious, he concluded he was a rascal, though he had known some instances of very good men being religious”.’