As a barrier to metastases, cells normally undergo apoptosis after they lose contact with their extra cellular matrix or their neighbouring cells. This cell death process has been termed “anoikis”. Tumour cells that acquire malignant potential have developed mechanisms to resist anoikis and thereby survive after detachment from their primary site and while travelling through the lymphatic and circulatory systems. Defects in the death receptor pathway of caspase activation, such as the over-expression of the caspase-8 inhibitor FLIP, can render cells resistant to anoikis. Likewise, roadblocks in the mitochondrial pathway, such as over-expression of the Bcl-2 family of anti-apoptotic proteins, can also confer resistance to anoikis. This review will focus on the roles of the death receptor and mitochondrial pathways in anoikis and anoikis resistance and how targeting defects in these pathways can restore sensitivity to anoikis and serve as the basis for therapeutic adjuncts that prevent metastasis.