Compliance with clinical practice guidelines is a challenging topic because it depends on a variety of factors, some related to guidelines themselves, some related to users, and some to the implementation context. Among the former are guideline quality, purpose and implementation modality. Among the userrelated factors are attitude to behavioural changes, authority interventions to foster adherence and eventually the type of users (general practitioners, hospital professionals, home caregivers, patients, etc.). Context is also crucial because organisational issues, such as lack of resources, can hamper guideline implementation and sometimes the original guideline intention is overridden by the guideline adaptation to a certain setting. This chapter analyses these factors and discusses their implications for the development of computerised decision support systems. Moreover, it gives examples of non-compliance detection and analysis in a specific real-world computerised guideline implementation, facing both methodological and practical issues.