: Next Generation Sequencing (NGS) Technology has represented a revolution in the molecular characterization of Inherited Retinal Dystrophies (IRDs), which are among the most genetically and phenotypically heterogeneous conditions. NGS has allowed the characterization of a consistent number of patients affected by IRDs, but at the same time, unexpected results can pose diagnostic dilemmas. : The purpose of this review is to describe possible scenarios as a reference for ophthalmologists and geneticists who are involved in this particularly complex field. : A review of the existing literature has been performed. In addition, examples have been brought, from a series of patients that have been analyzed at the University of Naples "Federico II"-CEINGE Biotecnologie Avanzate "Franco Salvatore". : Unexpected results in the genetic characterization of IRDs are not uncommon. The main findings are additional variants that potentially modify phenotypes, deletions masked by apparent homozygosity, and pathogenic variants leading to phenotypes revisitation. : The high genetic and phenotypic heterogeneity characterizing IRDs have been greatly advantaged by the advent of NGS Technology. At the same time, the not uncommon finding of unexpected data poses diagnostic criticisms that need to be addressed. In this review, we describe possible scenarios, and we go through some more complex genotype-phenotype correlations.