Adult daily smokers motivated to quit smoking will be randomized to extended-release guanfacine (6mg/day) or placebo and will enroll in an 8-week treatment period combining medication with brief behavioral support. The investigators hypothesize that the active dose of guanfacine compared to placebo will increase rates of prolonged smoking abstinence at the end of the 8-week treatment phase.

Inclusion Criteria:

• Age 18-65
• Able to read, write and comprehend English
• Smoker
• Able to take oral medications and willing to adhere to a medication regimen
• Provide evidence of a stable living residence in the last 2 months, have reasonable transportation to the study site, and have no plans to move within the next 3 months or unresolved legal problems

Exclusion Criteria:

• Any significant current medical conditions that would contraindicate smoking
• Current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) abuse or dependence of other substances, other than nicotine dependence or alcohol abuse
• Positive test results at intake appointment on urine drug screen for illicit drugs
• Past 30 days use of any psychoactive drugs including anxiolytics and antidepressants
• Women who are pregnant or nursing
• Suicidal, homicidal or evidence of current mental illness such as schizophrenia, bipolar disorder or major depression, or anxiety disorders
• Meeting DSM-IV criteria for current attention deficit hyperactivity disorder (ADHD)
• Individuals who are currently taking medications known to be effective for smoking cessation or are regular users of other tobacco products in the past 30 days
• Only one member per household can participate in the study
• Specific exclusions for administration of guanfacine not already specified include:
• EKG evidence at baseline screening for any clinically significant conduction abnormalities or arrhythmias
• Known intolerance for guanfacine or any alpha blocker
• History of fainting, syncopal attacks
• Heart failure or myocardial infarction
• Impaired liver (as indicated by aspartate aminotransferase (AST), alanine aminotransferase (ALT) >3x normal)
• Renal function (as indicated by estimated creatinine clearance <60cc/min)
• Treatment with any antihypertensive drug or any alpha-adrenergic blocker
• Use of any central nervous system depressant (e.g., phenothiazines, barbiturates, benzodiazepines)
• Use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin), or consumption of grapefruit juice
• Subjects may not have donated blood in the past 8 weeks or have been involved in other investigational studies that involve substantial blood draws or medications unknown to us

During 8-week treatment period.