In clinical practice, relatively little attention is directed towards identifying underlying causes and contributing factors to weight gain in patients with obesity. However, recognising these "hidden fattening factors" is important as it can lead to more effective treatment strategies. In particular if underlying causes can be solved first, this could help to realise sustainable weight reduction. Besides the well-known lifestyle-related aspects, obesity may be caused or maintained by medication use, endocrine or hypothalamic disorders, monogenetic or syndromic diseases, and mental factors, which may require specific (medical) treatment. For lifestyle-related obesity, a combined lifestyle intervention (CLI) is a first step to combat obesity. This treatment comprises intensive guidance regarding healthy nutrition, physical activity, and behavioural psychology. In case of morbid obesity and insufficient effects of CLI after one year, weight-reducing medication or a bariatric intervention can be considered. This systematic strategy for diagnostics and treatment of obesity is illustrated by two clinical cases.