Abstract Proteins operate within dense interconnected networks, where interactions are necessary both for stabilising proteins and enabling them to execute their molecular functions. Remarkably, the protein-protein interaction networks operating within tumour cells continue to function despite widespread genetic perturbations. Previous work has demonstrated that tumour cells tolerate perturbations of paralogs better than perturbations of singleton genes but the mechanistic means by which paralogs tolerate perturbation remain poorly characterised. Here we systematically profile the proteomic response of tumours and tumour cell lines to gene loss. We find many examples of both active compensation, where deletion of one paralog results in increased abundance of another, and collateral loss, where deletion of one paralog results in reduced abundance of another. Active compensation is enriched among sequence-similar paralog pairs that have high protein-protein interaction degree and that are widely conserved across evolution. Active compensation is also significantly more likely to be observed for gene pairs with a known synthetic lethal relationship. Compensating paralogs have more ubiquitination sites, suggesting a role for post-transcriptional control by protein degradation. Our results support a model whereby loss of one gene results in increased protein abundance of its paralog, stabilising the protein-protein interaction network. Consequently, tumour cells become dependent on the paralog for survival, creating potentially targetable vulnerabilities.