This chapter covers the basic principles of clinical pharmacology, focusing on the elderly and the role of pharmacotherapy in patients with comorbid mental and physical illnesses. Consideration of pharmacokinetic processes (liberation, absorption, distribution, metabolism, and elimination) helps improve the efficacy and safety of pharmacological treatments, especially for patients with comorbidities and polypharmacy. Since drug-drug interactions (DDIs) are a significant source of adverse drug events, the identification of potential DDIs may also contribute to better treatment of patients with comorbidities. Depression and physical comorbidities are discussed in detail in this chapter because depression is one of the most commonly diagnosed psychiatric disorders, and it is highly prevalent in patients with physical illnesses. In addition, the treatment of somatic conditions can induce secondary depression, and antidepressant medications have various somatic adverse effects. These complexities are summarized based on current evidence and specific clinical recommendations to help guide decision-making about the pharmacologic treatment of depression with somatic comorbidities. The short section on schizophrenia with somatic comorbidities emphasizes that, in addition to cardiovascular and metabolic diseases, infectious diseases, particularly pulmonary infections, are linked to higher mortality rates compared to the general population.