Julius Caesar has returned to Rome triumphant from the war against Pompey. The Roman republic is prepared to heap him with new honours, causing concern and dismay among some senators who fear that too much power is held by one man. Caius Cassius plots a conspiracy to murder Caesar, enlisting the support of the well-respected Marcus Brutus. Brutus has misgivings but is persuaded that Caesar's death is necessary for the good of the republic. However, he rejects Cassius' proposal that Mark Antony, close friend of Caesar, should also be killed. Brutus, Cassius and their co-conspirators stab Caesar to death at the senate house on the Ides of March. At Caesar's funeral Brutus addresses the people and successfully explains the conspirators' motives. However, Mark Antony speaks next and turns the mob against the conspirators, who are forced to flee from Rome. Mark Antony and Caesar's nephew, Octavius, take command of Rome and lead an army against the conspirators. Brutus and Cassius are defeated at Philippi where they kill themselves rather than be captured.
In 1584, the death of the duke of Alencon had left the French crown with a contested line of succession to Henri III. By 1588, contenders for the crown were Henri, king of Navarre, who was the protestant favourite, and Henri, duke of Guise, the Catholic favorite. He was sometimes referred to as "Caesar", and there was a four page comparison of Guise and Julius Caesar. The duke of Guise was a feudalist intent on preserving the role of the French nobility. De Vere was sympathetic to the duke of Guise, not least because of his views on the role of the nobility. In 1577, de Vere had sent servants to France to fight on Guise's behalf. In January 1588, under the king's orders, Guise was lured into a private antechamber at Chateau Blois and stabbed dozens of times by a squad of nobles. As Guise had been popular with the Catholic population, he was buried with much honor. Reports of supernatural events that gave warning of the impending assassination began to appear soon afterwards. Henri III then allied with the Protestant faction to crush the remnants of Guise's Catholic League. However, in August 1588, a fanatical monk stabbed and killed the king.
The play was likely started in 1588 or 1589. Various plays at the time echoed the phase "Et tu, Brute?". It was probably revised later in de Vere's life. Caesar, like de Vere, had excessive pride and gullibility. The assassins were generally likeable. There were no obvious winners in the play - perhaps a reflection of a mature playwright who saw things in many shades of gray, rather than black and white.