The ocular penetration pathways of three alpha 2-adrenergic agents (p-aminoclonidine, AGN 190342, and clonidine) were investigated in rabbits both in vitro and in vivo. The corneal permeabilities of the compounds correlated positively with their octanol/water distribution coefficients. The ocular drug absorption via corneal and conjunctival/scleral penetration routes was evaluated separately after drug perfusion in vivo. In most cases, the corneal route was the major pathway for the intraocular drug absorption. However, the conjunctival/scleral penetration pathway was the predominant pathway for the delivery of p-aminoclonidine, the least lipophilic compound among the three drugs, to the ciliary body. The drug concentration in the iris was contributed mainly by the corneal route and correlated well with drug lipophilicity.