The purpose of this study is to evaluate the impact of varenicline treatment on cue induced craving to smoking using brain imaging. The investigators hypothesize that participants will report reduced urges to smoke and will have less activation in parts of the brain associated with craving.

Treatment with varenicline reduces overall subjective cigarette craving and smoking reward in nicotine-dependent smokers. This preliminary study will explore the impact of varenicline treatment on smoking cue-induced craving and associated regional brain activation using BOLD fMRI. Twenty healthy smokers (10 males, 10 females) will undergo two BOLD fMRI scans with the presentation of smoking-related and neutral cues at baseline and after five weeks of treatment with open-label varenicline. The investigators hypothesize that participants will report reduced urges to smoke on the Questionnaire of Smoking Urges-Brief and have less activation of the brain areas associated with craving during the fMRI after 5 weeks of varenicline and smoking cessation counseling compared to the baseline scan.

Inclusion Criteria:

1. Age 21 - 60 treatment-seeking right handed smokers.
2. Meet criteria for primary nicotine dependence confirmed by FTND and smoked at least 70% of days in the last 30 days prior to assessment.
3. General good health confirmed by history & physical.
4. Able to read and understand questionnaires and informed consent.
5. Motivated to quit, willing to set a target quit date (TQD) and abstain from smoking after TDQ.
6. Participants must have a negative urine drug screen (UDS) and pregnancy test prior to imaging sessions and beginning varenicline treatment.
7. Female participants will use a reliable method of birth control throughout the study.
8. Demonstrate subjective response to cues in a laboratory cue reactivity session.

Exclusion Criteria:

1. Currently meets DSM-IV criteria for any other psychoactive substance dependence disorder except nicotine dependence.
2. Any psychoactive substance abuse within the last 30 days as evidenced by subject report or urine drug screen.
3. Use of other tobacco products.
4. Current use of nicotine replacement therapy, bupropion, or other smoking cessation treatment.
5. Previous failed attempt on varenicline.
6. Meets DSM-IV criteria for current axis I disorders of major depression, panic disorder, obsessive compulsive disorder, post-traumatic stress syndrome, bipolar affective disorder, schizophrenia, or any other psychotic disorder or organic mental disorder.
7. Current suicidal ideation with plan or homicidal ideation.
8. Need for maintenance or acute treatment with any psychoactive medication including anti-seizure medications which could potentially interfere with fMRI.
9. Clinically significant medical problems that would impair participation or limit ability to participate in scan.
10. Sexually active females of child-bearing potential who are pregnant, nursing, or who are not using a reliable form of birth control.
11. Has current charges pending for a violent crime (not including DUI related offenses).
12. Persons with ferrous metal implants or pacemaker since fMRI will be used.

AE's were collected over 5 weeks post medication administration.