Until now no extensive welfare research of transgenic farm animals has been requested and scientific insight in (methodological) problems specifically associated with investigating welfare of live-stock involved in genetic modification is limited. With a practical example of a transgenesis experiment in dairy cattle serving as a guideline, some of these problems are discussed. It is argued that, in case of generating transgenic livestock, we may be faced with systematic side-effects of reproductive technologies other than microinjection/genetic modification, superimposed upon essentially unpredictable, for each founder animal unique, side-effects of microinjection/genetic modification. In contrast with 'conventional' animal welfare research, research concerning welfare of genetically engineered animals lacks. as yet, comprehensive (theoretical) models allowing for hypothesizing about and the interpretation of the possible outcome of the treatment. Considering the transgenesis experiment in dairy cattle, three methodological problems are discussed, which may be exemplary for single transgenesis studies in general: (1) with manipulated (transgenic and non-transgenic) individuals originating from oocytes obtained at the slaughterhouse, genetic background from the maternal lineage is unknown (2) due to time-demanding experimental procedures, unbalanced animal material is obtained (3) A single transgenesis experiment yields very few transgenic individuals. It is suggested that, considering the heterogeneous outcome of the treatment microinjection/genetic modification, obtaining larger numbers of founder animals need not necessarily increase possibilities of reliably elucidating relevant treatment effects. In addition, appreciating welfare implications of genetic engineering may be difficult as biological change per se does not imply a change in welfare. It is proposed that systematically producing and screening founder animal progeny may be the most feasable experimental approach in evaluating harmful consequences of genetic modification. Causes and mechanisms underlying effects of treatments other than microinjection/genetic modification may be most efficiently investigated in studies addressing these treatments separately or in well balanced combinations. It is concluded that appropriate experimental strategies can only be achieved when fundamental insight is gained into the incidence and nature of possible treatment induced side-effects at the level of the genome.