Current medications have not been effective in reducing the prevalence of mental illness worldwide. The prevalence of illnesses such as treatment-resistant depression has increased despite the widespread use of a broad set of psychopharmaceuticals. Transcranial magnetic stimulation and ketamine therapy are making great strides in improving treatment-resistant depression outcomes but they have limitations. New psychotherapeutics are required that specifically target the underlying cellular pathologies leading to neuronal atrophy. This neuronal atrophy model is supplanting the long-held neurotransmitter deficit hypothesis to explain mental illness. Interest in psychedelics as therapeutic molecules to treat mental illness is experiencing a 21st-century reawakening that is on the cusp of a transformation. Psilocybin is a pro-drug, found in various naturally occurring mushrooms, that is dephosphorylated to produce psilocin, a classic tryptamine psychedelic functional as a 5-hydroxytryptamine 2A receptor agonist. We have focused this review to include studies in the last two years that suggest psilocybin promotes neuronal plasticity, which may lead to changes in brain network connectivity. Recent advancements in clinical trials using pure psilocybin in therapy suggest that it may effectively relieve the symptoms of depression in patients diagnosed with major depressive disorder and treatment-resistant depression. Sophisticated cellular and molecular experiments at the systems level have produced evidence that demonstrates psilocybin promotes neuritogenesis in the mouse brain - a mechanism that may address the root cause of depression at the cellular level. Finally, studies with psilocybin therapy for major depressive disorder suggest that this ancient molecule can promote functionally connected intrinsic networks in the human brain, resulting in durable improvements in the severity of depressive symptoms. Although further research is necessary, the prospect of using psilocybin for the treatment of mental illness is an enticing possibility.