Cancer is a multifaceted and genomically complex disease and rapidly accumulating high impact researchis deepening our understanding related to the mechanisms underlying cancer development, progression andresistance to therapeutics. Increasingly it is being realized that genetic/epigenetic mutations, inactivation oftumor suppressor genes, overexpression of oncogenes, deregulation of intracellular signaling cascades andloss of apoptosis are some of the extensively studied aspects. Confluence of information suggested that rapidlydeveloping resistance to therapeutics is adding another layer of complexity and overwhelmingly increasingpreclinical studies are identifying different natural agents with efficacy and minimal off-target effects. Wepartition this multi-component review into citrus fruits and their bioactive ingredients mediating rebalancingof pro- and anti-apoptotic proteins to induce apoptosis in resistant cancer cells. We also discuss how oncogenicprotein networks are targeted in cancer cells and how these findings may be verified in preclinical studies.