The accessibility to topical administration through inhalation, combined with its large surface area, has led to speculation that the lung might offer an ideal target for the application of oligonucleotide based therapeutics. In this review, we shall critically examine the challenges facing antisense and siRNA based approaches for target validation in vivo and as potential therapeutics. In particular, we shall discuss the antisense and siRNA based approaches in relation to factors such as delivery, distribution, stability, off-target effects, unwanted immune responses and the selection of the optimum mRNA targets.