<p>Hemodialysis, a cornerstone therapy for chronic kidney disease, represented a crucial advance in the evolution of artificial organs. While its success is largely due to its efficiency in removing uremic toxins, an equally important challenge is to uphold the <i>primum non nocere</i> principle by minimizing the harmful effects of membrane–blood interactions. This review examines the complex mechanisms and key interactions underlying membrane biocompatibility, including complement activation, inflammation, and coagulation disturbances, paving the way for their clinical implications. We also summarize recent innovations in membrane materials and surface engineering aimed at improving hemocompatibility and promoting safer hemodialysis treatments for improved clinical outcomes.</p>