Alfalfa (Medicago sativa L.) is a perennial, outcrossing legume crop predominantly grown for hay, silage, or pasture. Intensive selection has resulted in dramatic improvement in fitness traits, including winter survival and disease resistance. However, there has been minimal improvement in other economically important traits, such as hay yield, which is still comparable to 30 years ago. Intensive phenotyping costs on this type of trait hinder high selection pressure to identify superior outcross individuals. Severe inbreeding depression inhibits the development of inbred lines with accumulated favorable alleles that exhibit heterosis. This review highlights the outcomes of inbreeding depression as well as the causes, including unmasking deleterious alleles and triggering self-incompatibility. We tracked the research efforts that unveil the genetic bases underlying deleterious alleles and self-incompatibility. The magnitudes of inbreeding depression were compared with the rate of heterozygous halved time in diploid and tetraploid organisms. To fill in the gaps between the controversy and existing hypotheses, we theorized a dosage dominant model of inheritance. The dosage dominant model is similar to the Mendelian dominance model, in which a genotype exhibits a dominant phenotype if there is a dominant allele (alphabet dominant). The difference is that in the dosage dominant model, a genotype will result in a dominant phenotype if the number of dominant alleles is equal to or greater than the number of recessive alleles. This review also includes a discussion on the development of pseudo inbreds and a hypothesis to identify deleterious alleles using bulked segregant analysis and consequently to purge deleterious alleles using marker-assisted selection, to progress toward the successful development of pure inbred lines in alfalfa.