The homunculus was the first man-sized homunculus created by Edel Mischrasse in 1529. Mischrasse, however, fearing the religious authorities would soon discover him, poisoned the homunculus and abandoned him in a well in Wittenberg. The homunculus soon managed to will himself to life and went in search of his creator, eventually finding Mischrasse in a French prison. Mischrasse told the homunculus the location of the locked box containing his research notes on making homunculi, and the homunculus murdered his creator and took the key from Mischrasse's stomach.
The homunculus traveled to Albi to recover Mischrasse's notes. He knew the existence of a second homunculus created by Mischrasse, Roger, but did not try to find him, and instead concentrating on continuing his creator's work. He set up a lab in the burnt ruins of the Capatineni Monastery in Romania. The locals believed the monastery to be haunted, which allowed the homunculus the privacy he needed; the occasional noise and smell from his work only served to increase the fear of the locals. The homunculus' works was successful in creating smaller homunculi, which he used as his servants and put them to work robbing graves to provide raw material for his "great work" - the creation of a giant body.
By 1997, the homunculus soon learned of Roger's revival and found him and offer to invite him to join him in the giant body, to be one forever, never to be alone again - "to build, grow, climb, to crack wide the celestial vault and rake there for secret knowledge." Roger rejected his brother's offer, despite his desire for some connection after centuries of being alone. The homunculus took over the giant body for himself, and faced off against Hellboy. When the homunculus came close to killing Hellboy, Roger stopped him and begged his brother another chance, to become one with the giant. The homunculus swallowed Roger whole, but Roger used the fire stolen from Liz Sherman to melt the enormous body from within, thereby destroying the homunculus.