Recent research increasingly shows the relevance of network based approaches for our understanding of biological systems. Analyzing human protein interaction networks, we determined collective influencers (CI), defined as network nodes that damage the integrity of the underlying networks to the utmost degree. We found that CI proteins were enriched with essential, regulatory, signaling and disease genes as well as drug targets, indicating their biological significance. Also by focusing on different organisms, we found that CI proteins had a penchant to be evolutionarily conserved as CI proteins, indicating the fundamental role that collective influencers in protein interaction networks plays for our understanding of regulation, diseases and evolution.