Hondou Eisuke first appeared soon after one of Conan's confrontations with the Black Organization, in which it was revealed that popular newscaster Mizunashi Rena was one of their members. He enlisted into Teitan High School and quickly made friends with Mouri Ran and Suzuki Sonoko, who noticed the striking similarity to Mizunashi.
Some time later, Eisuke visited Ran's father in his office, where he also ran into Conan. After expressing a vivid interest in Mouri's work, he was invited by Ran to come by anytime, much to the displeasure of Conan, who had become suspicious of Eisuke. This suspicion was confirmed by the fact that in subsequent cases Eisuke made several blunders which would 'incidentally' contribute to the solution of the relevant case.
Eisuke is a person with extremely bad luck. He's constantly bumping into or falling over something. However, his clumsiness belies a sharp intellect and keen talent for observation: With only few clues to work with, he was able to track down his vanished sister to the Haido Central Hospital, where the FBI was keeping her under guard, and even penetrate the facility to confront Mizunashi Rena - who really was his sister Hondou Hidemi - before he was discovered by Conan. He figured out that Shinichi and Conan were the same person before even meeting Conan and managed to force to the truth out of him later.
In time, Conan found out that Eisuke was indeed related to Mizunashi. He had come to Tokyo looking for clues of his sister's whereabouts, sparked by him seeing her working as a newscaster by happenstance. He learned the truth from Conan, Hidemi and Akai Shuuichi that his sister, as well as his late father, were working for the CIA against the Black Organization.
Following this revelation, he was offered a place in the Witness Protection Program, which he refused, though he decided to follow in his family's footsteps by joining the CIA one day. Alone with Conan, he also confessed that he had fallen in love with Ran and wished to take her with him to America. When Conan protested, Eisuke laughed out loud, stating that Conan's reaction was the final confirmation he had needed: that Conan was really Kudou Shinichi, and that in fact he was responsible for the "Sleeping Kogoro's success." With this revelation, he asked Conan/Shinichi to take good care of Ran in his stead, thus promising to keep his secret.
