It is very unlikely that our obesity-promoting environment will change in the near future. It is therefore mandatory to improve our knowledge of the main factors associated with successful adoption of obesity-reducing behaviors. This may help design more powerful procedures and strategies to facilitate the adoption of healthy lifestyles in a “toxic” environment favoring the development of a positive energy balance. The aim of this review is to describe the main factors associated with successful adoption of obesity-reducing behaviors and to describe the most recent development, limits, and outcomes of lifestyle modification programs. The evidence regarding predictors of weight loss and weight loss maintenance remains largely incomplete. It is necessary to develop strategies matching treatments to patients’ needs to improve successful weight loss and its maintenance. How to detect and how to address these needs is a continuous, challenging, research problem.