This paper undertakes a broad and comprehensive synthesis of relevant clinical, biological, biomechanical, technical and healthcare services data to understand the factors affecting outcomes of periapical healing after root canal (re)treatment. The medical and dental evidence‐based era (1980–present) is contextualized with the earlier evidence drive in endodontics (1911–1940) triggered by the focal infection era. The current evidence‐based approach has a sharper focus on evidence quality and derivation of practice guidelines. Contrary views question whether guideline‐driven, or expertise‐development‐driven endeavours would best serve outcome improvement in society. The endodontic discipline functions in a broad healthcare framework and sustains industrial, economic and trend pressures that may be deemed to influence outcomes. The nature of root canal treatment and the challenges in determining the factors that affect its outcomes is discussed. The factors potentially affecting periapical healing after root canal treatment are classified into pre‐operative, intra‐operative and postoperative groups. These categories subsume multiple elements with interactive influences, creating a complex picture, further confounded by some apparently surprising, counter‐intuitive and contradictory findings. The technical versus biological conundrum in root canal treatment continues to cause cognitive dissonance. However, due reflection and cross‐discipline‐synthesis resolve the apparent data conflicts into a very simple, consistent and plausible picture of how root canal treatment works and the key factors that affect periapical healing. Root canal retreatment is considered mainly in the context of its differences from primary treatment as the majority of factors influencing outcomes are common to both. The exceptional difference is that retreatments have a proportionately reduced probability of healing by virtue of compromised apical root canal ramification access or modified host/infection interactions. Root canal (re)treatment outcomes are dominantly influenced by the nature of prior dynamic host/infection interaction (pre‐operative patient factors) and how the direction of this dynamic is influenced by two factors: (1) the active efficacy of the operators' root canal treatment protocol to sustain a microbial ecological shift (intra‐operative treatment factors) and dampen periapical inflammation; and (2) the passive ability of the functional tooth (and its restoration margin) to maintain its integrity to resist infection reversal (postoperative restorative factors).