In 58 BC, when consul, he and his colleague, Aulus Gabinius, entered into a compact with Publius Clodius, with the object of getting Marcus Tullius Cicero out of the way. Piso's reward was the province of Macedonia, which he administered from 57 BC to the beginning of 55 BC, when he was recalled. Piso's recall was perhaps in consequence of the violent attack made upon him by Cicero in the Senate in his speech De provinciis consularibus.
Caesar mentions his father-in-law in his Gallic Commentaries. Piso's grandfather, also named L. Calpurnius Piso, was killed by the same Gauls that Caesar would later conquer.
On his return, Piso addressed the Senate in his defence, and Cicero replied with the coarse and exaggerated invective known as In Pisonem. Piso issued a pamphlet by way of rejoinder, and there the matter ended. Cicero may have been afraid to bring the father-in-law of Julius Caesar to trial. At the outbreak of the civil war, Piso offered his services as mediator. However, when Caesar marched upon Rome, he left the city by way of protest. Piso did not openly declare for Gnaeus Pompeius Magnus but remained neutral and did not forfeit the respect of Caesar.
After the murder of Caesar, Piso insisted on the provisions of Caesar's will being strictly carried out and, for a time, he opposed Marcus Antonius. Subsequently, he became one of Anthony's supporters and is mentioned as taking part in an embassy to Antony's camp at Mutina with the object of bringing about a reconciliation with Octavian.
The maxim fiat justitia, ruat coelum ("Let justice be done, though the heavens fall"), used by Lord Mansfield in the James Somersett case and in the alternate form fiat iustitia, et pereat mundus by Ferdinand of Habsburg, is sometimes attributed to Piso, but this is disputed – see fiat justitia, ruat coelum article for details.