Abstract: Methods for selecting single or multiple aptamer pairs against target molecules in free solution have been developed. These methods utilize novel cooperative evolution approaches to select aptamer pairs against one or more targets, in which the pairing of one or more aptamers upon target binding triggers aptamer amplifiability. In this manner, the enrichment of aptamer ligands through one or multiple rounds of the selection process is based predominantly upon target-driven close proximity of aptamers in free solution. Target binding and enrichment are coupled using either positive or negative selection methods. These techniques should be generally applicable to many different types of target molecules, providing alternatives to antibodies, drugs, or other binding molecules for analytical, preparative, and therapeutic purposes.