Metastasis is the final stage of cancer progression and is responsible for more than 90% of cancer related deaths, claiming millions of lives worldwide. The most formidable challenge in the treatment of metastatic cancer is the emergence of resistance to current therapies. Informed by clinical data and using functional in vivo and in vitro models our group seeks to understand the mechanistic determinants for cancer progression, defined by metastatic competence and resistance to therapies. Both rely on programs that ensure the cancer cells’ survival during periods of enhanced cellular stress, limited survival cues and attacks by the immune system. Although fascinating and clinically important, mechanistic insights into these programs are still lacking. Our ultimate goal is to enhance the efficacy of current anti-cancer therapies using combinatorial treatment regimens and find new therapeutic avenues to fight metastatic cancer.