What struggles do transgender and gender-nonconforming (TGNC) individuals report around religion and spirituality (r/s), and what types of r/s beliefs, experiences with religion, and gender-identity-related factors make such struggles more likely? Our sample (N = 315) came from a larger online study in which we contacted over 700 sources (websites, email lists, and social media) to recruit TGNC adults, mostly from North America and Western Europe. Participants (most identifying as Caucasian) endorsed a diverse range of gender identities (e.g., transgender, nonbinary, genderqueer, gender fluid, agender, and gender nonconforming). About half reported some past rejection by religious communities. The majority (58%) had exited traditional monotheistic religions (especially Christianity) or were never religious (24.6%), with many now identifying as atheist, agnostic, or nonreligious and others choosing personal spiritual paths or Earth-spirited faiths (Wicca or paganism). Participants generally reported modest levels of r/s struggle. Interpersonal struggles were most prominent, followed by ultimate meaning, doubt, moral, divine, and demonic, respectively. In a regression analysis, rejection by religious communities, God's perceived disapproval of one's gender identity, seeing God as causing one's gender identity, and internalized transphobia all uniquely predicted more r/s struggle, even when controlling religiousness, gender minority stress (distal and proximal), self-esteem, and trait resilience. In other regressions, r/s struggle (especially ultimate meaning) predicted more proximal gender minority stress (transphobia, nondisclosure, and negative expectations), even when controlling distal gender minority stress (nonaffirmation and history of discrimination/rejection/victimization), religiousness, self-esteem, and trait resilience. We suggest that r/s struggles warrant closer examination in research and clinical work with TGNC individuals.