Rejection is never easy. You’ve put long weeks, months, maybe even years of work into a project that you think is perfect to publish in Nature Methods, so your feelings of disappointment, anger, frustration or self-doubt are completely understandable. Your first instinct might be to hit “reply” and send an angry email to the editor. But your best bet is to take some time to cool off, then move on and submit the paper elsewhere. If you are convinced, however, that a serious error has been made or that you can fully address the specific criticisms raised by the editors or by referees, then you may send a constructive appeal letter to the editor.