Pissuthnes was born as the son of a man named Hystaspes. The two names are remarkable, because they are purely Zoroastrian. The father is otherwise unknown, but may have been a member of the Achaemenid dynasty that ruled the Persian empire. However this may be, it is certain that in 440, Pissuthnes was satrap of Lydia. He served the interests of his king Artaxerxes I Makrocheir (465-424) by supporting the oligarchs of Samos, who had revolted against Athens, the Greek town that regularly attacked the Persian possessions in Asia Minor. However, the Athenians were able to suppress the rebellion of their ally.
During the Archidamian War (431-421), Athens and Sparta, the other leading Greek power, were at each others throats. Pissuthnes repeated his policy between 430 and 428, when he supported the Athenian ally Colophon against its master by sending mercenaries to the town. Next year, when the Greeks of Lesbos rose in rebellion against Athens, they could offer Sparta a treaty with Pissuthnes. However, the Athenians were able to prevent the escalation of the Lesbian revolt.
In 420, Pissuthnes revolted against king Darius II Nothus (423-404). We do not know why. The king sent a nobleman named Tissaphernes to Lydia, and he was able to incite a rebellion among Pissuthnes' Greek mercenaries. Having achieved this, he offered negotiations. When Pissuthnes arrived at the place of the talks, he was arrested, sent to the king and executed.
Tissaphernes succeeded Pissuthnes as satrap of Lydia (ca.415). During his first years, he still had to fight against Pissuthnes' son Amorges, who continued the struggle with Athenian help. It was probably this Athenian intervention in Persian territory that made king Darius II side with Sparta in the Decelean or Ionian War (413-404).