A method for generating a mutein of human apolipoprotein D having detectable affinity to a given non-natural ligand of apolipoprotein D is disclosed, which comprises the steps of: (a) subjecting the apolipoprotein D to mutagenesis at the sequence positions 34 to 38, 60, 62 to 66, 68, 89 to 93, 115, 117 to 121, and 123 resulting in a plurality of muteins of apolipoprotein D; and (b) enriching resulting muteins having binding affinity for a given ligand from the plurality of muteins by selection, and/or isolating said mutein. Muteins of apolipoprotein D obtainable by this method are also disclosed.