Targeting activated kinases as a therapeutic modality in cancer was initiated with the dramatic success of imatinib for treatment of chronic myelogenous leukemia. Early success was observed where clear evidence linked the genomic alteration, in the form of constitutively activated fusion protein kinases, such as bcr-abl, or mutations causing constitutive enzyme activation, such as EGFRmut or BRAFmut. The genomic event created a driving enzymatic process. More recently, new enzyme targets have been identified through looking at more downstream and indirect events which are still important in process of cancer progression. Kinases involved in angiogenesis are a strong example with approvals worldwide for treatment of renal cell cancer and neuroendocrine cancers, amongst others. Enzymes, such as polyADPribose polymerase (PARP), have also been demonstrated to be both biologically necessary and targetable, leading to the class of PARP inhibitors used in ovarian and other cancers. While these downstream associated pathways are also successful targets, the strength of the impact on the treated cancers is less than observed with the more central drivers. This has led to a broad array of combination approaches. The hypothesis expected improved outcome with inhibition of points in series or in parallel in a pathway, or pathways where regulation of one sensitizes the other. Success has been observed with the combination of BRAF inhibition with MEK inhibition, two nodes in series within the RAS/ERK pathway. Early results demonstrated greater benefit with inhibition of VEGFR kinase in combination with bevacizumab. And, a strong example is found in PARP inhibitor combinations. Data demonstrate that the PI3K pathway may activate DNA repair, in part negating the role of PARP inhibition. The combination of PI3K and PARP inhibition, in vitro, in vivo and in preliminary clinical studies demonstrated activity in unexpected patient populations and awaits more definitive evaluation. Addition of cediranib, a VEGFR 1-3 kinase inhibitor, to PARP inhibition with olaparib resulted in markedly improved benefit, especially for those patients not expected to benefit from PARPi. Hypoxia, such as that induced by use of VEGFR kinase inhibitors, has been shown in vitro to downregulate expression of key enzymes in the homologous recombination DNA repair pathway. Thus, use of cediranib creates a BRCA-like background, synergizing with PARP inhibition. The combination of olaparib and cediranib in women with platinum-sensitive ovarian cancer yielded an almost 2-fold increase in progression-free survival. A nearly 3-fold benefit was observed for those women without germline BRCA1/2 mutation, who would be expected to have limited benefit from olaparib alone. Analysis of hypoxia in a limited subset of the study patients showed a strong correlation between progression-free survival and induction of circulating endothelial cell precursors, a recognized marker of hypoxia. In this case, one plus one has yielded much more than two, and we await completion of the combination in ongoing definitive studies in both platinum-sensitive and platinum-resistant ovarian cancer.