The outcome of fascial plane blocks (FPBs) has a certain variability that may depend on many factors, which can be divided into three main categories: operator-related, patient-related and drug-related. Operator-related factors include personal skills, choice of needle and injection modalities. Patient variables include anthropometric features, the type of targeted fascia, anatomical variants, patient positioning, muscle tone and breathing. Ultimately, efficacy, onset, and duration of fascial blocks may be affected by characteristics of the injected solution, including the type of local anesthetic, volume, concentration, pH, temperature and the use of adjuvants. In this article, we investigated all the factors that may influence the outcome of FPBs from a generic perspective, without focusing on any specific technique. Also, we provided suggestions to optimize techniques for everyday practitioners and insights to researchers for future studies.