This study investigates the multiplicity of thioredoxin (Trx) systems in *Clostridioides difficile*, a gut pathogen and model for Clostridia. The authors analyzed the composition and regulation of Trx systems across bacteria, finding that while most bacteria have a single NAD(P)H-dependent TrxB, some Clostridia, particularly those in the Firmicutes phylum, have multiple TrxBs, including ferredoxin-dependent TrxBs. In *C. difficile*, the 630Δ*erm* strain contains three TrxA and three TrxB genes. The study demonstrates that two Trx systems are crucial for survival under infection-related stresses, such as oxygen, inflammation-related molecules, and bile salts. A fourth TrxB copy in some strains also contributes to stress response. One of the conserved stress-response Trx systems is present in both vegetative cells and spores, regulated by both vegetative cell and sporulation sigma factors. This system helps protect spores from hypochlorite and ensures proper germination in oxygen. Another Trx system, involving TrxA3 and TrxB3, is involved in glycine catabolism and sporulation. The multiplicity of Trx systems and the diversity of TrxBs likely meet specific needs in Clostridia for adaptation to strong stress exposure, sporulation, and Stickland pathways. The study provides insights into the physiology of *C. difficile* and the complexity of Trx systems in Clostridia.This study investigates the multiplicity of thioredoxin (Trx) systems in *Clostridioides difficile*, a gut pathogen and model for Clostridia. The authors analyzed the composition and regulation of Trx systems across bacteria, finding that while most bacteria have a single NAD(P)H-dependent TrxB, some Clostridia, particularly those in the Firmicutes phylum, have multiple TrxBs, including ferredoxin-dependent TrxBs. In *C. difficile*, the 630Δ*erm* strain contains three TrxA and three TrxB genes. The study demonstrates that two Trx systems are crucial for survival under infection-related stresses, such as oxygen, inflammation-related molecules, and bile salts. A fourth TrxB copy in some strains also contributes to stress response. One of the conserved stress-response Trx systems is present in both vegetative cells and spores, regulated by both vegetative cell and sporulation sigma factors. This system helps protect spores from hypochlorite and ensures proper germination in oxygen. Another Trx system, involving TrxA3 and TrxB3, is involved in glycine catabolism and sporulation. The multiplicity of Trx systems and the diversity of TrxBs likely meet specific needs in Clostridia for adaptation to strong stress exposure, sporulation, and Stickland pathways. The study provides insights into the physiology of *C. difficile* and the complexity of Trx systems in Clostridia.