Manuscript rejected? Breath. You're in good company.
I remember one particular soccer practice with my brother when I was 6 years old. It's memorable because he kicked the ball really hard and directly into my solar plexus. I stopped breathing and still vividly recall thinking that I would die. Working on a project for 4-5 years and getting your first rejection letter from the journal editor feels very similar. The good news is that the next time you get the rejection letter (hopefully on a different paper), you are depressed and angry, but you no longer think you will die. Of all the papers I published, my two most significant contributions were both rejected (my main graduate paper by PLOS Genetics and my main postdoc paper by PNAS).
The really good news if you just got a rejection is that you are apparently in terrific company. My former labmate Nikolai Slavov has put together a wonderful post on the rejections of seminal research papers (including the rejection by both Nature and Science of Kary Mullis's PCR work).
Nikolai's piece reminded me of the rejection letters of famous literary authors (such as Nabokov's Lolita, Kerouac's On the Road). The first Harry Potter was rejected by all 12 publishers who received it from J.K Rowling. Also fun and uplifting to spend some time going through literary rejections at onehundredrejections.com. And back in the science world: How Are the Mighty Fallen: Rejected Classic Articles by Leading Economists.
Clearly, rejection is not exclusive to biomedical research. So write a good rebuttal, or say "fuck you" to the journal like Mullis did, and to soften the blow of future rejections, make sure to post your pre-print on bioRxiv.