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Psychiatric disorders affect about half of the cancer patients. A majority of oncology patients suffer psychosocial distress and chemotherapy-induced nausea and vomiting during the course of their disease, 50% and 75%, respectively. Adjustment disorder is the most frequent diagnosis, followed by major depression. In cancer patients, the choice of a psychotropic drug is a challenge that must target ‘not to harm’. Indeed, those patients are more vulnerable to drug interactions because of their physical fragilities (poor nutrition, weight loss, other medical conditions, young or advanced age), multimedication and possible enzyme deficit due to genetic polymorphisms or iatrogenic causes. Therefore, the choice of psychotropic drugs must be cautious, minimizing the possible increase in adverse side effects and the decrease in the efficacy of drugs which are crucial to the treatment of cancer. Antipsychotics are frequently used for the treatment of delirium and for the prevention of chronic nausea due to chemotherapy while antidepressants and anxiolytics are used for cancer-related mood and anxiety disorders. Haloperidol is often used sedative drug, particularly in the treatment of nausea, vomiting and delirium, including terminal agitation. In addition olanzapine is safe and highly effective in controlling acute and delayed nausea and vomiting in patients receiving highly emetogenic and moderately emetogenic chemotherapy. The pharmacokinetic drug interactions with antidepressants are unlikely with busulfan, chlorambucil, estramustine, mechlorethamine, melphalan, temozolomide, 5-şuorouracil, gemcitabine, mercaptopurine, thioguanine, cisplatin, carboplatin, oxaliplatin, daunorubicin, doxorubicin, epirubicin and vorinostat. Among the chemotherapeutic agents, tamoxifen is the one more extensively studied for drug interactions with antidepressants. Tamoxifen is a selective modulator of estrogen receptors. In women with breast cancer and at the initial stage, the use of tamoxifen has been associated with a reduced risk of recurrence at about 1/2 and death risk by breast cancer at about 1/3. Because both tamoxifen and selective serotonin reuptake inhibitors (SSRI) are metabolized by CYP2D6, SSRI inhibition of CYP2D6 activity could reduce tamoxifen prevention of breast cancer recurrence. Paroxetine, şuoxetine and bupropion are strong CYP2D6 inhibitors which should be avoided in tamoxifen users. Venlafaxine, mirtazapine, citalopram and escitalopram are small inhibitors of CYP 2D6, therefore being a safe choice when using tamoxifen. Most of the other anticancer drugs subjected to metabolization by CYP 450 3A4 should be used with caution concomitantly with inhibitors of this isoenzyme such as şuoxetine, sertraline, paroxetine and şuvoxamine. Escitalopram, citalopram, venlafaxine, mirtazapine and milnacipran are antidepressants with minimal CYP 450 inhibitory potential and are therefore safer in these patients. Venlafaxine is also efficacious for the treatment of hot şashes in combination with tamoxifen. Gabapentin is also efficacious in treating tamoxifen-induced hot şashes and, since it does not interact with cytochrome P450 system, is likely safe to use in patients using tamoxifen. Pregabalin may be alternatives to venlafaxine and gabapentin, respectively, in this population. Tricyclic antidepressants are used in the management of neuropathic pain. Benzodiazepines may be treated simultaneously nausea, pain, and anxiety. As they treat anticipatory anxiety and phobia, they mitigate anticipatory nausea and a component of post-treatment nausea.