Negative consequences of inbreeding have been subject to intensive research for over a century. Yet, major improvements of knowledge on identifying detrimental mutations and estimating inbreeding depression have been achieved only recently as a result of high-throughput DNA sequencing developments. The main objective of this review was to explain methodological changes following as a consequence of new molecular developments. Regression of phenotypes on pedigree inbreeding coefficients (F_PED) has been the standard procedure applied in quantifying inbreeding depression in animals and humans. Being a genome wide expectation, F_PED neglects stochastic variations and the impact of selection on the regional autozygosity. This further implies that regression analysis based on F_PED suits well for traits that can be approximated by the infinitesimal model with dominance. In contrast, runs of homozygosity (ROH) inbreeding coefficient (F_ROH) is able to quantify autozygosity of chromosomal regions, or even a single SNP. For genetic analysis this is quite a large conceptual difference where F_ROH opens new standpoints in identifying or/and estimating the effects of chromosomal regions, genes, or even a single SNP mutations that sizably contribute to the inbreeding depression. Here, we systemized the methods used in the identification or/and estimation of negative consequences of inbreeding with respect to the genetic architecture of the analyzed trait. Emphasis was given to (1) ROH-based mapping of loci contributing to inbreeding depression as a concept that has already been applied in livestock and human research, and to (2) SNP-wise dissection of inbreeding depression as a new theoretical concept. While the first concept is targeted toward the identification and estimation of detrimental mutations segregating in a population, the second concept is derived to improve the understanding of the molecular basis of inbreeding depression (functions of genes, dominance versus overdominance, distribution of gene effects). At the end, we discuss the potential use of predicting detrimental load from the whole-genome sequences, as well as of applying the gene editing in reducing the inbreeding load.