[3] Between 1316 and 1320 Gui acted as Procurator General of the Dominican Order, representing its interests within Pope John XXII's court at Avignon, and during this time he also undertook diplomatic missions on behalf of the papacy.

[9] Gui's inquisitorial work took place in the Languedoc, a region that remained a "stronghold of heresy", in particular Catharism, despite the church's repeated efforts in the area throughout the thirteenth century (such as the Albigensian Crusade of 1209–1229).

)[10] The inquisitor would then hold a 'general sermon' (sermo generalis), assembling the local populace and publicly declaring the names of those judged guilty of the sin of heresy and their concomitant penances.

As canon law prohibited the clergy from spilling blood, those who refused to repent or who had relapsed into heresy were handed over to the secular authorities for punishment, typically execution by burning at the stake.

[15] In the early fourteenth century inquisitorial activities were also characterised by increased attention to unconverted Jews, and in 1319 Gui arranged for copies of the Talmud to be publicly burnt in Toulouse, a tactic commonly used by Dominican inquisitors.

[13] Gui was one of the most prolific Latin authors of the Late Middle Ages, although he rarely wrote original works, preferring instead to compile and arrange existing texts, anecdotes, and records.

He ordered the construction of a library at Limoges to accommodate over one hundred volumes; this was completed in 1306 and represented "one of the earliest efforts in the West to build a room devoted especially to the preservation of books".

Additionally, he completed and significantly expanded the De Quator in quibus Deus Praedicatorum ordinem insignivit, a historical treatise on the Dominican Order begun in the 1270s by Stephen of Salanhac, and uncompleted at the time of the latter's death in 1291.

Inquisitors had no standardised or formal training, although they were often educated in theology or law, and practical guides to inquisitorial activities emerged as a distinct literary genre in the late twelfth century.

[22] Gui's manual consisted of five books: the first three were formularies, providing templates to be used to deliver sentences during 'general sermons', and the fourth reproduced documents outlining and confirming the powers of the inquisitor (such as papal and conciliar legislation, and royal decrees).

The fifth and most famous book provided descriptions of the beliefs and practices of heretics such as Cathars (referred to as 'modern Manicheans'), Waldensians, Pseudo-Apostles, Beguines, and relapsed Jews, in addition to guidance for inquisitors on the best methods of interrogation for each group (including advocating torture if necessary).

[28] A fictionalised Gui features as a secondary antagonist in the best-selling 1980 historical novel The Name of the Rose (Il nome della rosa) by Italian scholar and cultural critic Umberto Eco; the book has been translated into more than thirty languages and sold over fifty million copies.