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Intrinsic resistance is an innate characteristic shared across a species, rather than a response to prior drug exposure or newly acquired resistance genes. It is generally associated with stable chromosomal features. Mechanisms include reduced drug entry through an outer membrane, constitutive efflux, absence or alteration of a drug target, inactivating enzymes, and metabolic bypass. Examples illustrate how these mechanisms affect treatment options: Mycoplasma lacks peptidoglycan and is therefore resistant to cell-wall-active β-lactams, while anaerobes have poor aminoglycoside uptake. Some organisms also have characteristic intrinsic resistance linked to porins, efflux pumps, or enzyme production. Biofilms can further reduce antimicrobial activity through diffusion barriers and slow growth. Understanding these patterns supports more informed consideration of antimicrobial choice.