The direct approach in molecular diagnosis proposes evidences of the mutations underlying the investigated diseases. Due to its speed, specificity and low cost, the Polymerase Chain Reaction (PCR) has become the method of choice in most of these analyses. The direct approach can be either positive or negative. In the first case, the diagnosis is based on the presence of a pathognomonic PCR product, while in the latter, it is the absence of such a product that makes the diagnosis possible. It is evident that both methods have to be validated by several control reactions. Examples out of daily practice illustrate various diagnostic areas.