Cyanide & Happiness is a webcomic that was started in the 2000s, created by Kris Wilson and his associates (collectively "Explosm Entertainment"). Its creators have been featured multiple times on The First Podcast.
Kris Wilson, Dave McElfatrick and Rob DenBleyker have all made guest appearances on The First Podcast, with each getting their own episode.
As a lifelong fan of the comic, Joe was particularly ecstatic to have them on, considering them "dream guests". Joe often brags about them being the biggest guests on the show, since they have tens of millions of followers, and over 2 billion views on YouTube as of June 2019.