We describe here the use of the ELISA spot assay to identify, quantify, and isolate rare hybridoma subclones that have switched to expressing a new class or subclass of Ig. This technique is less labor intensive and time consuming than sib selection and standard ELISA and eliminates the many false positives that complicated those techniques. The use of the ELISA spot assay also allows screening large populations of cells and accurate quantitation of the rate of isotype switching.