The majority of patients treated for cancer will have pain at some point in their journey. It will be due to thedisease (e.g. bone metastasis, fracture, organ invasion) or from iatrogenic causes (chemotherapy, surgery orradiation). A large number of patients will also have depression. Since pain and depression share commonbiological pathways and even neuro-transmitters it is not surprising that a comorbidity of pain is depression. Ithas already been reported that patients in severe pain are 4 times less likely to respond to therapy for depression.In recent years, especially in the era of molecular biology and post-genomic a wealth of data in the arena ofpharmacogenetics/genomics has shed more light on cancer related symptoms such as pain and related them tothe cytokine pathways, especially the interleukins and tumor necrosis factor (TNF). When we remember thatthe synonym for TNF is ‘cachectin’ it is no wonder patients feel awful when there is active disease and the bodytrying to mount a response. Neuroendocrine, immunomodulatory and inflammatory pathways are likelyimportant in the pathophysiology of pain and depression. These realizations are in addition to a greaterunderstanding of afferent pathways for pain perception, of the multiple opioid receptors, the effects of hormonesand catechol metabolism and other transmitters. Moreover we already have a more complete under-standing ofdrug metabolism, especially of the opioids, the back bone of all pain treatment. There are a number of singlenucleotide polymorphisms (SNPs) in the genes important for drug metabolism such as CYP2D6, a cytochromeresponsible for about 25% of all drugs. There are about 90 variants already reported and rapid and slowmetabolizers need very different doses of codeine or morphine. We are entering an era of having the capabilityto develop personalized treatment for our patients’ nociceptive pain, neuropathic pain and depression. Theconvergence of new knowledge in the molecular biology and pharmacogenetic era should allow us to treat ourpatients’ suffering with a resultant increased quality of life even while we strive to cure them of their malignancy.