The advent of new immunostains have improved the ability to detect limbic and cortical Lewy bodies, and it is evident that dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, after Alzheimer’s disease (AD). Distinguishing DLB from AD has important implications for treatment, in terms of substances that may worsen symptoms and those that may improve them. Neurocognitive patterns, psychiatric features, extrapyramidal signs, and sleep disturbance are helpful in differentiating DLB from AD early in the disease course. Differences in the severity of cholinergic depletion and type/distribution of neuropathology contribute to these clinical differences.