The main theme of "Angels in America" is what it was like to be a gay man in the mid-1980s. The story takes place during the height of the AIDS epidemic and as such, the disease is a predominant theme throughout, affecting the lives of several of the main characters. Transformation is a major theme that affects every main character. Harper, a Republican politician's wife, exemplifies this theme in her transformation from a sheltered woman who is afraid of the changing world around her to an independent figure who is realistic and even optimistic about the changes that lie ahead.

Change is also a theme in Louis's life as he struggles to accept the reality of his partner's terminal illness. Even as he embraces the theme of change on an intellectual level, he runs from it in his personal life. Louis's partner Prior also deals with change in the form of abandonment. Despite the fact that change means losing everything, Prior holds fast to the idea that to be human is to change and that stasis is good for no one.

The themes of change and transformation are also exemplified in Joe's quest to come to terms with his own sexuality. By marrying Harper and pursuing a career as a conservative politician, Joe attempted to transform himself into the man he was raised to be. As the story progresses, he is forced to choose between true transformation into the person he really is and stagnation in the identity he has created for himself.