The Crusade began officially when the High Lords of Terra authorize Lord Militant Golgenna Angevin to liberate the areas around the Calyx Expanse. His forces draw from Segmentum Solar, number over 17 million troops divided into four battle groups and a strategic reserve plus Space Marines from the Black Templars, Sons of Medusa, Tigers Argent, and Charnel Guard. Titan Legions from the Legio Venator and Legio Magna also contribute to the Crusade's cause. The forces are further swelled by Frateris Militia stirred into a frenzy by the Ecclesiarchy. The Crusade's first strike is conducted in a two-pronged thrust into the heart of the Calyx Expanse, Malfi and Solomon by the end of 341.M39.
The two worlds fall quickly, giving the Crusade a bridgehead. Three minor Xenos empires are defeated from these anchors. In light of its success, the High Lords authorize further reinforcements. Seizing the moment, the Crusade launches a gigantic sweeping offensive throughout the years of 341-545.M39 in an event known as the Reaping of the Emperor's Wrath. Known worlds to fall in the Reaping are Loacanthos, whose warlord regime fell to General Drusus in a single week. Exterminatus is enacted on the world of Amun'an Morrus, where the once-human population has since become mutated into hideous machines. With the first and second great phases of the Crusade completed, by 353.M39 Angevin's forces consolidate their holdings, over two hundred worlds. Several Imperial Guard regiments which have shown valor in the preceding fighting are given the right to settle newly acquired worlds, such as the Brontine Centurions. 
In 359.M39, the Crusade's Second Front opens. A third great push from Segmentum Obscurus under the command of High Admiral Vaakkon. Intending to meet up with Angevin's forces, this phase of the Crusade proves disastrous after Warp conditions worsen. When the fleet finally links up with the Crusade's primary front in 363.M39, the losses it has sustained are nearly equal to the first two decades of fighting. Lord Militant Angevin is so horrified by this turn of events that he retreats to the interior of Golgenna Reach and passes on command to his senior generals.
The Bleak Years
With the Crusade now stalled, its domains come under attacks from Orks and xenos raiders. Assassins claim the life of Arch-Confessor Melcher El, the Crusade's spiritual leader. Plague decimates the Malfian Holdfast and rebels and cults spread. For the first time the Crusade's gains begin to be lost, and Imperial forces spread themselves thin to defend their remaining holdings. Only the fleets of the Rogue Traders Sibylline Haarlock and Ludd Sabrehagen provide rapid transport and redeployment of forces, allowing for some progression in an offensive by General Drusus against the Warp-worshiping Yu'vath xenos and their debased human allies. Drusus is declared the Crusade's savior, but many power figures view him as a dangerous rival.
According to some sources, Drusus is then attacked by assassins deployed by rival generals. Seemingly slain, he is seemingly resurrected as a Living Saint which makes many see him as having the Emperor's favor. Drusine Imperial Cult begins to flourish. Meanwhile, the Ordo Malleus oversees the decimation of the Yu'Vath and their allies. With the Crusade reinvigorated, a new great push begins, destroying the powers in a region that would become known as the Drusus Marches in his honor. In 372.M39, Angevin dies, with rumors suggesting he had been dispatched by the Officio Assassinorum for his failings. Drusus is promoted to Lord Militant and given full command of the crusade. With his new position, Drusus launches a final offensive against the Yu'vath Hell Worlds. By 384.M39, the Yu'vath are finally wiped out and the Crusade ends. The Calyx Expanse is claimed for the Imperium.