Purpose of Review <p>Lyme disease (LD) is a tick-borne spirochetal infection that can follow a temporal evolution affecting multiple systems over a period of weeks to months. Lyme arthritis (LA) is a late complication and can have a remitting and relapsing course. Early antimicrobial therapy can reduce LD sequalae and effectively treat LA. Despite a lack of evidence of microbial persistence in the treated host, significant controversy exists from misplaced associations of post- treatment syndromes with persistent LD/LA.</p> Recent Findings <p>Following appropriate treatment of LA, exaggerated host immunological responses can cause persistent symptoms in absence of the <i>Borrelia Burgdorferi</i> spirochete which are either self-limiting or respond to anti-inflammatory therapies. Long-term nonspecific constitutional symptoms (“post-treatment Lyme disease”) have no pathophysiologic basis and do not warrant antibiotics.</p> Summary <p>Infectious disease specialists have an important role to play in provider and patient education regarding the pathogenesis of LD, correct interpretation of diagnostic tests and avoidance of prolonged antibiotics in late LD.</p>