A long time after the events of "Final Frontier", Pyro and Isaac return to the Mass Effect universe, this time during the events of Mass Effect 2's Tali'Zorah loyalty mission. Due to some botched cloning efforts on the part of Cerberus following the death of Commander Shepard, there are two Shepards active: the original has become the female Shepard, with red hair and the [url=http://blogs-images.forbes.com/davidthier/files/2012/04/Femshep-Hair-Color-400x314.jpeg]standard looks of the Mass Effect 3 version[/url] in N7 armor, while the second, a clone, is the standard looks of the male version, in the highest available grade of Cerberus armor, currently their Assault Armor (later to be upgraded to their Ajax suit). However, both Shepards remain of the Soldier class.

Initially, Isaac meets with Kairi and Cheryl Mason in the Normandy SR-2, reuniting with the crew as a whole, and meeting the new members. After some talk, he and Cheryl agree to date. Isaac is given Kestrel Armor and a Collector Assault Rifle, while Cheryl gets a later-replaced X-27 Scimitar c shotgun and a suit of Collector Armor, and Kairi, for her outer-space travels, obtains a suit of Blood Dragon Armor. The crew meets with Pyro Mireu (wreathed in flames to keep from infecting the ship) on board the Rayya, the key ship of the Migrant Fleet of the quarians, and, through their travels, manage to call out the entire Admiralty Board repeatedly for their actions, getting Tali off on her treason charges without giving any evidence, and leave soon afterwards, having obtained the new name of Tali'Zorah vas Normandy for the quarian squadmate and her loyalty and trust.