All adaptive alleles in existence today began as mutations, but a common view in ecology, evolution, and genetics is that non-neutral mutations are much more likely to be deleterious than beneficial and will be removed by purifying selection. By dramatically limiting the effectiveness of selection in experimental mutation accumulation lines, multiple studies have shown that new mutations cause a detectable reduction in mean fitness. However, a number of exceptions to this pattern have now been observed in multiple species, including in highly replicated, intensive analyses. We briefly review these cases and discuss possible explanations for the inconsistent fitness outcomes of mutation accumulation experiments. We propose that variation in the outcomes of these studies is of interest and understanding the underlying causes of these diverse results will help shed light on fundamental questions about the evolutionary role of mutations.