High-risk prescribing involves medications with narrow therapeutic indices, significant drug-drug interactions, high potential for adverse events, or complex dosing requirements that demand advanced clinical judgment. Understanding pharmacokinetic principles (absorption, distribution, metabolism, excretion) and pharmacodynamic principles (drug-receptor interactions, dose-response relationships) is essential for safe prescribing. Narrow therapeutic index (NTI) drugs such as warfarin, digoxin, lithium, phenytoin, and aminoglycosides have small margins between therapeutic and toxic serum levels. Genetic polymorphisms in cytochrome P450 enzymes (CYP2D6, CYP2C19, CYP3A4) create significant interpatient variability in drug metabolism: poor metabolizers accumulate drugs to toxic levels, while ultra-rapid metabolizers may not achieve therapeutic concentrations. Polypharmacy (≥5 concurrent medications) exponentially increases the risk of drug interactions, adverse effects, and medication errors. The Beers Criteria identifies potentially inappropriate medications for older adults, while the STOPP/START criteria guide evidence-based prescribing decisions in geriatric patients. Controlled substance prescribing requires understanding opioid metabolism, equianalgesic dosing, morphine milligram equivalents (MME), and addiction risk stratification. The CDC guideline recommends limiting opioid doses to <50 MME/day for chronic pain and avoiding concurrent benzodiazepine-opioid prescribing due to synergistic respiratory depression.