Methods and compositions are provided for enriching for target sequences from a population of nucleic acids, that includes combining in solution, a population of nucleic acids and a target isolation probe wherein the target isolation probe includes an affinity binding domain; permitting a single stranded region of the target isolation probe to hybridize to all or a portion of a target sequence in the population of nucleic acids; selectively immobilizing the hybridized nucleic acids from the population containing the target sequences by associating the target isolation probe with a capture domain and removing unbound material; and removing from the 3′ end of the target sequence, a non-target sequence by means of one or more 3′ single strand specific exonucleases. Target enrichment may be used to detect variations in nucleotide sequence for detecting phenotypic changes related to health or disease.