Skullito is a floating skull creature who attacks by shooting green orbs from his eyes (similar to the fire from Gilead's Gun) while also spewing Spiders from his mouth. If not disposed of quickly, he can spawn a large amount of spiders in a short period of time, which can be a problem for weapons such as the Crossbow, Trident, and Sickle.
Although it is easy to kill Skullito with many different weapons, the grenade launcher (or bombs if not available) worked best from both a damage standpoint and for crowd control. Shooting (or throwing) mainly when Skullito starts spitting up spiders to both kill the spiders and to damage Skullito.
He is the first boss impelemented into the game