If you work with protein sequences you can reach out to more distant orthology relationships.
In my experience, using HMMER's jackhmmer tool to search for homology of a query protein against aset of target proteins is the approach that gives the most distant relations.
BLAST+ is a very good option in terms of speed/sensitivity if you proteomes are not extremely distant.OrthoMCL is a good option for simplicity of use.
If the two proteomes or sets of cdnas are close like human-chimp, it is important to be able to separateone-to-one from one-to-many from many-to-many orthologues, and for that using gene trees usuallyhelps. There was a recent method published that is specially important for the analysis of gene trees forclosely related species, called DLCoal:http://www.ncbi.nlm.nih.gov/pubmed/22271778
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