The Milesian philosophers—Thales, Anaximander, and Anaximines—set up a pattern of questions that all later Presocratic philosophers then tried to answer. The first and most fundamental of these was the question: what is the most basic or underlying substance of the world?

This question, the question of physis, can actually be broken down into two separate questions. The search for a physis is, first of all, a search for some substance out of which everything else in the world arose. In this sense, we might say that according to modern science the physis of the world is subatomic particles. Everything in the world, as far as we know, is built up out of these particles.

The search for a physis is also the search for a unifier within nature—either for some substance that is the most basic constituent of the world and of which everything else is somehow a variation, or else for some pattern through which all things in the world form a unity. For the Presocratics the physis was either one or the other of these—i.e. either some basic constituent or some lawlike pattern. To try once again to apply the physis problem to modern science, today we would probably say that the physis, in this second sense, is both a basic constituent (again the subatomic particles) and a lawlike pattern (the laws of quantum mechanics that govern the behavior of these subatomic particles).

Thales, as the first philosopher, was the first to treat the physis problem. According to Thales the physis of the world is water. But water was only Thales' physis in the first sense—as the substance out of which everything else arose. From the sparse fragments that remain to us of Thales' thought, it does not appear as if he considered the second part of the physis problem, the problem of a unifier within nature. Anaximander, a student of Thales, proposed a different physis. His physis was an infinite, indefinite substance, that he referred to as the "apeiron." The apeiron, like all the later candidates for physis, was meant to be a physis in both the above senses.

Anaximander's student Anaximines theorized that the physis was something he called "aer," an infinite substance, but not an indefinite one. Aer, is like a thick, misty air. For Xenophanes there were two physis, earth and water. Heraclitus was the first to propose that the unifier in nature was not some basic material constituent, but rather some structure, law, or plan within nature. He called this structure the "logos" and believed that it controlled the entire natural world.

For Parmenides there was only a single real thing in the world, the unified, unchanging, unmoving reality, and so there really was no need for a question of physis. The Pluralists, however, who tried to revive natural philosophy in Parmenides' wake, returned to the physis problem. According to Empedocles the physis were the four elements, for Anaxagoras the physis was an infinite number of homeomeric substances (i.e. substances without differentiated parts), and for the Atomists, the physis were tiny, indivisible, imperceptible atoms.