The topic of guilt and shame is explored across the podcast episodes, with guests and callers grappling with the emotional aftermath of personal and professional failures, betrayals, and life-altering events.

In the episode "Stephen Dubner and the Joy of Quitting", the host and guest discuss how the fear of failure and shame of quitting can hold people back from pursuing new opportunities. The episode "My Husband Fell in Love With His Therapist" addresses the guilt and shame experienced by a caller whose husband's affair with his therapist has fractured their relationship.

Across the episodes, the theme of guilt and shame as a response to trauma, loss, and identity struggles emerges, underscoring the complex and often debilitating impact these emotions can have on an individual's mental health and personal growth.