He is a transhumanist who believes in the improvement of humanity through enhancement. Due to his studies of parasites, Fitz and Simmons seek his help with counteracting Hive's abilities, but he is kidnapped by Hive first to help recreate the original Kree experiment that created the Inhumans. After a S.H.I.E.L.D. raid on Hive's base, Radcliffe escapes and agrees to cooperate with Coulson and Talbot. After being acquitted, Holden begins work on transferring his artificial intelligence AIDA to a Life-Model Decoy, an old S.H.I.E.L.D. project.
Radcliffe experiments with Life-Model Decoys and uses the S.H.I.E.L.D. agents May, Coulson, Mack, Mace, Daisy, and Fitz, as well as himself, as subjects. With AIDA working as his assistant, he worked on a project called the Framework, which aimed to transfer peoples' consciousness from their mortal beings into this new reality. It is revealed that he modeled AIDA after his ex-girlfriend, Agnes Kitsworth, who was living with a brain tumor. He sought to relieve her suffering by transferring her consciousness into the Framework. However, he lost control of AIDA, who slashed his wrists and inserted him into the Framework, which was actually an alternate reality ruled by HYDRA. The Framework took away the one major regret of the subject, which ensured the subject would be loyal to the Framework. However after losing Agnes in the Framework as well to AIDA, who called herself Ophelia in there, he began to regret his efforts to force the S.H.I.E.L.D. agents into the Framework. He reforms, giving Daisy a backdoor out and and helping Simmons by tricking Fitz, Ophelia's love interest in the Framework, to leave. After Yo-Yo goes into the Framework to save Mack, he assists her in getting out as the Framework shuts down. Being already dead in the real world, he gives a last toast on a beach before he disappears along with the rest of the Framework.