Senator Kennedy was escorted down the Senate aisle by the Senior Senator from Massachusetts, Leverett Saltonstall, on January 3rd 1953, thereby launching Jack's career as Senator. During his first term, Kennedy concentrated his efforts in two areas: economic development and foreign affairs. To be an effective Senator and expand his horizons Kennedy would need strong staff.

The Senator's initial task was to put together an effective office staff He continued to rely on the same staff that had worked well for him in the House and added two key advisors, who would stay with him even through to his Presidency: Evelyn Lincoln became his personal secretary, and Theodore Sorenson became his second legislative assistant (and would eventually become his celebrated speechwriter, advisor, and special counsel.)

Senator Kennedy developed a comprehensive plan to advance the economic development of New England, issuing a 159-page book called, "The Economic Problems of New England: A Program for Congressional Action" . It included forty different proposals that would strengthen the economy of the region. Over the coming years most of the proposals were passed by the Congress.

Senator Kennedy supported plans for the St. Lawrence Seaway Project. New England legislators traditionally opposed this project, as it was feared it would benefit Great Lake Ports, at the expense of New England. Kennedy stated "it was good for the US, and thus, ultimately good for the country as a whole. " In a Senate speech supporting the seaway, Kennedy quoted Daniel Webster, "Our aim should not be States dissevered, discordant or belligerent, but one country, one Constitution, one destiny."

Kennedy was willing to attack the Eisenhower Administration's defense policy. He criticized the large cuts in conventional defense spending, and opposed Eisenhower's reliance on the strategy of massive nuclear retaliation for any conventional attack.

In foreign affairs, Kennedy was a strong critic of French policies in Indochina. He felt that by not granting independence to the Indochinese states, France was insuring a Communist victory. In a speech on the Senate floor, on April 6, 1954, Kennedy stated: "To pour money, material and men into the jungles of Indochina, without at least a remote prospect of victory, would be dangerously futile and self-destructive€¦" and, "No amount of American military assistance in Indochina can conquer an enemy, which is everywhere, and at the same time nowhere; an enemy of the people, which has the sympathy and covert support of the people. "

Kennedy continued to be highly critical of European colonial activities. He came out in 1958, in public opposition to the French refusal to grant Algeria independence. Kennedy also spoke out forcefully for increased ties to Israel.

Kennedy took a strong stand against a Constitutional amendment that would have eliminated the Electoral College. His forceful opposition to changing the electoral system was considered essential in rallying opposition to the change in the electoral system.

Kennedy tried to sidestep the sensitive issue of Senator McCarthy. He was reluctant to attack the Senator. When asked what he thought of McCarthy, Kennedy stated: "Not very much, but I get along with him. When I was in the House, I used to get along with Marcantonio and Rankin. As long as they don't step in my way, I don't want to get into personal fights. " Kennedy was between a rock and a hard place on this issue. His father was a strong McCarthy supporter, and his brother Robert was the McCarthy committee's chief counsel. Kennedy's constituents, however, were, by and large, firmly opposed to McCarthy's methods. As McCarthy veered more and more to the extreme, it became clear that Kennedy would have to take a stand. But, on October 10th, 1954, as a censure motion wound its way towards a vote in the Senate, Jack entered New York's Hospital for Special Surgery to undergo both lumbosacral and sacroiliac fusions. After the surgery, complications developed, and Senator Kennedy slipped into a coma. His condition was considered so critical that he received Last Rites He did, however, slowly begin to recover from this latest brush with death.

On December 2, 1954, the vote to censure McCarthy took place, while Senator Kennedy was still recuperating. He could have made it his business to return to the Senate to vote, but became, instead, the only Democratic senator not to vote for the censure.

This was Kennedy's worse but not only illness during his time in the Senate. But following the introduction of oral therapy for his Addison's disease, his health slowly stabilized.

In 1955, Kennedy, wrote the book, "Profiles in Courage" , together with his closest aide, Theodore Sorenson. The book provides an historical analysis of the acts of political courage exhibited by eight Senators over the course of US history. "Profiles in Courage" was an instant success and in 1957, Senator Kennedy received a Pulitzer Prize for the book.

That year, journalist and muckraker Drew Pearson charged that Kennedy had not written the book, and it had in fact been ghostwritten for him. Using the services of Washington lawyer Clark Clifford, Kennedy was able to obtain a retraction from Pearson, though the facts of this matter remain unclear to this day. What is known, however, is that Theodore Sorenson did much of the research, and helped with the writing. Kennedy clearly supervised the job, however, and contributed much of the writing. How great Sorenson's role really was in writing the book will never be truly known.