Ten divergent homologs were identified using a subtractive bioinformatic analysis of 12,614 cattle placenta expressed sequence tags (ESTs) followed by comparative, evolutionary and gene expression studies. Among the ten divergent homologs, eight have not been identified previously. These were named: cattle cerebrum and skeletal muscle-specific transcript 1 (CSSMST1), cattle intestine-specific transcript 1 (CIST1), hepatitis A virus cellular receptor 1 amino-terminal domain containing protein (HAVCRNDP), prolactin-related proteins 8, 9 and 11 (PRP8, PRP9 and PRP11) and secreted and transmembrane protein 1A and 1B (SECTM1A and SECTM1B). In addition, two previously known divergent genes were identified, trophoblast Kunitz domain protein 1 (TKDP1) and a new splice variant of TKDP4. Nucleotide substitution analysis provided evidence for positive selection in members of the PRP gene family, SECTM1A and SECTM1B. Gene expression profiles, motif predictions, and annotations of homologous sequences indicate immunological and reproductive functions of the divergent homologs. The genes identified in this study are thus of evolutionary and physiological importance and may have a role in placental adaptations.