Isaac was married to Tamara. They were married for eight years, and lived near Lincoln, Nebraska. Something supernatural killed their daughter, which they never found out why or how; but this might have been what caused he and Tamara to begin hunting things. He also expressed his dislike for Sam and Dean, because they didn't prevent the door to Hell from opening.
They met up with Sam, Dean, and Bobby at a house where a family mysteriously died. At the hideout, they told the gang they don't hunt with others especially with the damned fools who let the Devil's Gate get opened in the first place. Later, while chasing the demon Envy into a bar, he and Tamara go head first into a trap the demons set up. He dies at the hands of the demon Gluttony who made him drink Drano. A demon, presumably Wrath, then possessed his corpse to try and trick Tamara, but she stabbed him with a stake made of Palo Santo, immobilizing the demon. The demon was then exorcised by Bobby.
After the battle, Tamara gave Isaac a hunter's funeral.