The Dutch Medicines Act and the Medical Treatment Contracts Act (WGBO) form the legal framework for off-label prescribing. These acts are complemented with position statements and guidelines of professional organizations. However, this legal framework is not yet sufficiently embedded in daily practice. The explicit translation of the legal conditions into practical stepwise guidance can therefore provide important guidance when prescribing off-label. This article describes a step-by-step guide for responsible off-label prescribing. The step-by-step guide ensures that decisions about off-label use of drugs are made based on a deliberate and explicit consideration of the unmet medical need and alternative treatment strategies against the potential risks and benefits for the individual patient. In addition, the step-by-step guide ensures the correct provision of information to patients. In this way, the step-by-step guide enables the doctor to meet the regulatory requirements on the off-label prescription of drugs. In addition, we need better information provision on off-label use and professional consensus on information and consent obligation in order to be able to prescribe even more effectively off-label.