Although benefiting from an unprecedented technological evolution, contemporary endodontics is still characterized by the recurrence of retreatments, due to the need to solve quite frequent incidents, accidents, or even failures of primary endodontic treatment. This survey aims to assess both the etiology and the prevention methods of one of the most troublesome endodontic iatrogenies: instrument separation during root canal shaping. The multifactorial nature of this occurrence entails identifying and taking into account all the causal and contributing factors. Their significant number and the possible involvement of any of them, starting with the complexity and variability of the root canals and ending with the technical specifications concerning the nickel-titanium rotary instrumentation system being used, highlight the necessity to develop valid guidelines to avert the occurring of such an upsetting situation.