Šiškauskas was a physical forward (198 cm or 6'6" tall) who could easily play, both on offense and defense, at the guard positions, on the wing, and also in the paint. His excellent leaping ability and his quickness made him a surprising shot blocker and one of the best one-on-one players and swingmen in Europe. The best defensive player of the Lithuanian national basketball team; he led the 2003-04 Lithuanian League in free throw percentage (90.6%).
Šiškauskas made his pro debut with Sakalai in 1996. He played two seasons with the club, averaging 11.3 points, on 60 percent shooting.
In 1998, Šiškauskas signed with Lietuvos Rytas of Vilnius. He played there until the 2003-04 season, and led the team to Lithuanian League titles in 2000 and 2002, and a Northern Europe League title in 2002. In 2002-03, he had his most successful season, averaging 16.4 points, on 68 percent shooting, and 3.4 rebounds.
In 2006, Šiškauskas signed with Panathinaikos, and helped them win the Euroleague in 2007. He averaged 11 points, on 51 percent shooting for the championship team. With Panathinaikos, he also won a Greek League title and the Greek Cup in 2007.
Šiškauskas joined CSKA Moscow in 2007. He helped to lead them to a Euroleague title in 2008, and helped them reach the Euroleague Final in 2009. However, CSKA lost to Šiškauskas' former team, Panathinaikos. On May 1, 2009, he scored a career-high 29 points against Barcelona. Šiškauskas also won two Russian Super League titles in 2008 and 2009.
On May 15, 2009, Šiškauskas signed a contract extension with CSKA. He signed through 2011. Šiškauskas said: "I feel like the right man in the right place in CSKA. I am happy with both the team and the organization. That is why I don't see any reason to think about changes. I feel myself as a part of history of a great club, which is aiming for the highest goals. And that's what absolutely matches with my character."
On May 13, 2012, Šiškauskas missed two vital free-throws with 10 seconds remaining in CSKA's Euroleague Final game against Olympiacos Piraeus, which proved crucial in CSKA's 62 to 61 loss. He also missed the last second three-point shot in CSKA's Euroleague Final game against Panathinaikos, on May 3, 2009, which meant that CSKA lost the final by a score of 73 to 71.
Only one week after the Euroleague Final game, on May 21, 2012, Šiškauskas announced his retirement from professional basketball. On May 16, 2014, Šiškauskas was named a Euroleague Basketball Legend.