Replicative immortality is a hallmark of cancer, driven by activation of telomere maintenance mechanisms (TMM), that is yet to be therapeutically exploited. To expedite discoveries that will enable development of TMM-targeted therapeutics, we have generated a resource of telomere biology metrics for a pan-cancer panel of 976 cell lines. We have also produced new proteomic data from data-independent mass spectrometry for most of these cell lines. These data link to pre-existing multi-omic data, drug sensitivity and molecular dependency data from CRISPR/Cas9 knock-out screens for most cell lines. The TMM data illustrate a previously unappreciated range and heterogeneity in telomere biology measures, including telomere biology states that diverge from the binary model of TMM activation involving either telomerase or Alternative Lengthening of Telomeres (ALT). The multi-omic data were applied in conjunction with the TMM data to derive proteomic and transcriptomic predictors of ALT and telomerase activity levels. Our investigations also revealed molecular vulnerabilities of ALT cancer cells and identified an investigational drug, Pevonedistat, with activity that strongly correlates with telomerase activity levels. These discoveries illustrate the potential for leveraging this new resource of telomere biology metrics to realise the potential for TMM-directed cancer therapeutics and companion diagnostics.