At the end of the 6th century BC, Darius ruled over an immense realm. But the conquest of Asia Minor left the Ionian Greeks under Persian rule, while the other Greeks were free, a state of affairs that was going to cause trouble sooner or later.
In 499 BC, instigated by Aristagoras in Miletus, the Ionian Revolt broke out; Ionian cities threw out the "tyrants" that the Persians had set over them, formed a league, and applied for help from the other Greeks. Athens sent twenty ships and Eretria five, and the fleet helped spread rebellion all along the coast. In 498 the Greeks captured and burnt Sardis, thereby requiring a Persian response in the form of an invasion. The Greek fleet was crushed at the Battle of Lade in 494, and the Ionian cities sacked, although they were permitted to have democratic governments afterwards.
In 492, Mardonius overran Thrace and Macedonia, followed in 490 by the punitive expediation of Datis and Artaphernes. The islands of the Cyclades surrendered, Eretria was captured, and the expedition landed in Attica near Marathon. Phidippides got the message for help to Sparta in record time, but in the end the Athenians and Plataeans alone defeated the Persians in the battle of Marathon.
In 480, Darius' successor Xerxes I mounted a massive expedition, consisting of perhaps 100,000 soldiers and 1,000 ships. A preliminary diplomatic offensive secured the surrender of Thessaly, Delphi, Argos, and much of central Greece. Opposed to Xerxes was a Greek league led by Athens and Sparta, and a fleet hastily built by Themistocles. Attempts to hold back the Persians, at Thermopylae and Artemisium, both failed. Athens was evacuated, and the Greek fleet withdrew to Salamis. While the Peloponnesians proposed a defensive line at the Isthmus of Corinth, Themistocles instead engaged the Persian fleet at the Battle of Salamis, destroying most of their ships. Xerxes and his fleet retired to Asia, leaving Mardonius winter over in Thessaly with the army.
The following spring (479), Mardonius twice offered Athens a separate peace, but was rebuffed. Maneuvers in Boeotia, particularly cavalry harassment of the 38,000 Athenian and Peloponnesian hoplites, ended with the Battle of Plataea; Mardonius was killed, and his army routed. The remnants of the Persian army left Greece. Also in this year a Greek fleet commanded by the Spartan king Leotychides destroyed the remaining Persian fleet in the battle of Mycale.
Encouraged by Xerxes' failures, the Greeks of Asias and the islands revolted again. In 478, a fleet under Pausanias captured Byzantium and started a rebellion in Cyprus. At this point the Peloponnesians withdrew from involvement (apparently due to various disputes), but Athens carried on, forming the Delian League. The records become scanty, but Cimon destroyed a Persian army and fleet around 467. About 459 Athens sent 200 ships in support of a revolt in Egypt, although after driving the Persians up the Nile, the fleet was lost in a counterattack at Memphis ca. 454. Another expedition in 450 failed to revive the Egyptian rebellion, and Cyprus was abandoned.
Around 449/448, with the support of Pericles, Callias negotiated the Peace of Callias with the Persians. While the exact nature of the agreement remains unclear (formal treaty or non-aggression pact), the result was independence for the Greeks of Asia, Persian rule for Cyprus, and the closure of the Aegean to Persian warships.
The Persians never really renounced their ambitions, and continued to meddle in Greek affairs in a sort of "cold war"; seducing cities with diplomacy and/or buying them off with gold, and employing Greek mercenaries (most famously Xenophon), until Alexander put an end to the Persian empire. For the Greeks, the Persian Wars engendered a consciousness of Greek unity, but the reality was short-lived, and a mere twenty years later the Greek world was torn apart by the Peloponnesian War.