This journal issue contained free access of the 43rd European Mathematical Genetics Meeting (EMGM) 2015 ; New technologies such as Next Generation Sequencing have allowed investigation of the aetiology of diseases not previously amenable to genetic analyses due to their rarity, small family size and/or locus heterogeneity. For Mendelian diseases, relatively small numbers of small pedigrees are often sufficient to reduce the candidate risk mutations to a manageable number. Of the estimated 7,000 rare severe disorders, approximately half have now had risk genes identified for them [1]. This has left a rump of rare disorders whose aetiology may be resistant to such study designs. Study design for such diseases is hampered not only by ignorance of their aetiology, but also by the number and variety of assays available, and the typically high per subject cost of such assays. Researchers of rare diseases on constrained budgets may be limited not so much by the availability of disease cases as by assay costs, making assay choice a critical issue. We have developed a framework for assay choice that maximises the number of true disease causing mechanisms ‘seen’, given limited resources. Although straightforward, some of the ramifications of our methodology run counter to received wisdom on study design. We illustrate our methodology with examples, and have built a website allowing calculation of quantities of interest to those designing rare disease studies [2]. ; link_to_OA_fulltext