Werner syndrome (WS) is one of three heritable human genetic instability/cancer predisposition syndromes that result from mutations in a member of the gene family encoding human RecQ helicases. Cellular defects are a prominent part of the WS phenotype. Here we review recent work to identify in vivo functions of the WS protein and discuss how loss of function leads to cellular defects. These new results provide clues to the origin of cell lineage-specific defects in WS patients and suggest a broader role for Werner protein function in determining disease risk in the general population.