Chromosomal translocations have been identified that are consistently associated with alveolar rhabdomyosarcoma and Ewing’s sarcoma. Molecular diagnostic assays for these chromosomal translocations are important tools for the differential diagnosis of pediatric small round cell tumors presenting in the bones or soft tissues. However, the occurrence of variant chromosomal translocations in these cancers has complicated these molecular diagnostic approaches. To simplify the molecular detection of typical and variant translocations, the authors have developed an approach consisting of consensus reverse transcriptase-polymerase chain reaction and oligonucleotide hybridization steps. In the first step, consensus primers for each tumor type permit amplification of the chimeric transcripts resulting from both the common and variant translocations. In the second step, the common and variant translocations are distinguished by hybridization with gene-specific oligonucleotide probes. This approach provides a sensitive, specific, and efficient strategy for the detection of these chromosomal translocations.