标题的剧情是取自于圣经中上帝要求亚伯拉罕献祭自己长子以撒以测试他对上帝的信仰，在他举起刀时候被天使阻止这个故事。灵感来自于开发者本人孩童时期接受的家庭宗教习惯。
国内的玩家能够理解这个游戏的宗教背景，但难以感受它承载的重量——毕竟宗教在美国是日常生活的一部分。但是这个游戏在国外爆红之后引发英美主流媒体的报道，和游戏的圣经主题以及包含的黑暗成人内容是不无关系的。
但麦克米兰也不希望圣经要素仅仅成为一个噱头，他希望把它作为一个平台，探讨其他游戏避之不及的成人议题——虐童、堕胎、杀婴、自杀（随便哪个都要下地狱的）。在这里贴一段麦克米兰本人的自述。来自于游戏的postmortem:
I strongly believe that game enthusiasts want what they haven't seen yet, and that ***** gamers should be treated like *****s. Some people might argue that Isaac isn't "mature" when it comes to its content, but those people would be ignorant fools! When I designed Isaac's story and overall theme, I went in wanting to talk to the player about religion in a manner I was comfortable with -- that is, with dark humor and satire.
A lot of the content in Isaac is extremely dark and *****. It touches on aspects of child abuse, gender identity, infanticide, neglect, suicide, abortion, and how religion might negatively affect a child, which are topics most games would avoid. I wanted to talk about them, and I wanted to talk about them in the way I was comfortable with, so that's what I did with Isaac.
I'm not saying everyone who played Isaac did so because they cared about these themes, or that they even understood why they were in the game, but I strongly believe that this ***** conversation I dove into with Isaac is what made the game stand out to people and kept them thinking.
I grew up in a religious family. My mom's side is Catholic, and my dad's side is born-again Christians. The Catholic side had this very ritualistic belief system: My grandma could essentially cast spells of safe passage if we went on trips, for example, and we would light candles and pray for loved ones to find their way out of purgatory, and drink and eat the body and blood of our savior to be abolished of mortal sin.
As a child growing up with this, I honestly thought it was very neat -- very creative and inspiring. It's not hard to look at my work and see that most of the themes of violence actually come from my Catholic upbringing, and in a lot of ways I loved that aspect of our religion. Sadly, the other side of my family was a bit more harsh in their views on the Bible; I was many times told I was going to hell for playing Dungeons & Dragons and Magic: The Gathering (in fact, they took my MtG cards away from me), and generally condemned me for my sins.
I wanted Isaac to embody this duality I experienced with religion. I wanted it to show the positive and negative effects it had on me as a child -- the self-hate and isolation it instilled in me, but also the dark creativity it inspired. The Bible is a very good, creatively written book, and one of my favorite aspects of it is how so many people can find different meanings in one passage. I wanted Isaac to have this in its story as well, which is why the game's final ending(s) have many possible interpretations.