Cancer is fundamentally a genetic disease, characterised by mutations that permit or drive cancer growth. A rapidly expanding understanding of the genetic architecture of cancers is increasingly linked to rational cancer drug development. Of more than 800 molecules in drug development globally, more than 90% are directed towards a specific target. The use of comprehensive genomic profiling to guide treatment of cancer patients is the centrepiece of national precision oncology programs in many countries globally, including TAPUR (US), CAPTUR (Canada), DRUP (Netherlands), LC-SCRUM (Japan), and MOSCATO (France). The combination of evolution of drug development and access to affordable genomic profiling is enabling the most rapid evolution of cancer treatments in history. Here I will provide a progress update on the MoST program, a national genomic screening and signal-seeking trials platform that has enrolled more than 4,000 Australians with advanced cancers.